Publication number  US7754723 B2 
Publication type  Grant 
Application number  US 11/478,462 
Publication date  Jul 13, 2010 
Filing date  Jun 28, 2006 
Priority date  Dec 30, 2003 
Fee status  Paid 
Also published as  CA2551862A1, CN1902178A, DE602004019576D1, EP1727801A1, EP1727801B1, US20070032500, WO2005066130A1 
Publication number  11478462, 478462, US 7754723 B2, US 7754723B2, USB27754723, US7754723 B2, US7754723B2 
Inventors  Qun Sun, Laykea Tafesse 
Original Assignee  Purdue Pharma, L.P., Usa 
Export Citation  BiBTeX, EndNote, RefMan 
Patent Citations (32), NonPatent Citations (69), Referenced by (5), Classifications (30), Legal Events (3)  
External Links: USPTO, USPTO Assignment, Espacenet  
This application claims the benefit of U.S. provisional application No. 60/533,037, filed Dec. 30, 2003, and International patent application no. PCT/US2004/042732, filed Dec. 17, 2004, the disclosure of each application being incorporated by reference herein in its entirety.
The present invention relates to Nitro(cyano)vinylpiperazine Compounds, compositions comprising an effective amount of a Nitro(cyano)vinylpiperazine Compound and methods for treating or preventing a condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Nitro(cyano)vinylpiperazine Compound.
Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually selflimited, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100107 (J. C. Bennett and F. Plum eds., 20th ed. 1996)).
Moreover, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injuryinduced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the peripheral or central nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at both Group I mGluRs (mGluR1 and mGluR5) (M. E. Fundytus, CNS Drugs 15:2958 (2001)) and vanilloid receptors (VR1) (V. Di Marzo et al., Current Opinion in Neurobiology 12:372379 (2002)) to pain processing. Inhibiting GluR1 or mGluR5 reduces pain, as shown by in vivo treatment with antibodies selective for either GluR1 or mGluR5, where neuropathic pain in rats was attenuated (M. E. Fundytus et al., NeuroReport 9:731735 (1998)). It has also been shown that antisense oligonucleotide knockdown of mGluR1 alleviates both neuropathic and inflammatory pain (M. E. Fundytus et al., British Journal of Pharmacology 132:354367 (2001); M. E. Fundytus et al., Pharmacology, Biochemistry & Behavior 73:401410 (2002)). Small molecule antagonists for mGluR5attenuated pain in in vivo animal models are disclosed in, e.g., K. Walker et al., Neuropharmacology 40:19 (2000) and A. Dogrul et al., Neuroscience Letters 292:115118 (2000)).
Nociceptive pain has been traditionally managed by administering nonopioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. In addition to the abovelisted treatments, neuropathic pain, which can be difficult to treat, has also been treated with antiepileptics (e.g., gabapentin, carbamazepine, valproic acid, topiramate, phenyloin), NMDA antagonists (e.g., ketamine, dextromethorphan), topical lidocaine (for postherpetic neuralgia), and tricyclic antidepressants (e.g., fluoxetine, sertraline and amitriptyline).
Urinary incontinence (UI) is uncontrollable urination, generally caused by bladderdetrusormuscle instability. UI affects people of all ages and levels of physical health, both in health care settings and in the community at large. Physiologic bladder contraction results in large part from acetylcholineinduced stimulation of postganglionic muscarinicreceptor sites on bladder smooth muscle. Treatments for UI include the administration of drugs having bladderrelaxant properties, which help to control bladderdetrusormuscle overactivity. For example, anticholinergics such as propantheline bromide and glycopyrrolate, and combinations of smoothmuscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic, have been used to treat UI (See, e.g., A. J. Wein, Urol. Clin. N. Am. 22:557577 (1995); Levin et al., J. Urol. 128:396398 (1982); Cooke et al., S. Afr. Med. J. 63:3 (1983); R. K. Mirakhur et al., Anaesthesia 38:11951204 (1983)). These drugs are not effective, however, in all patients having uninhibited bladder contractions. Administration of anticholinergic medications represent the mainstay of this type of treatment.
None of the existing commercial drug treatments for UI, however, has achieved complete success in all classes of UI patients, nor has treatment occurred without significant adverse side effects. For example, drowsiness, dry mouth, constipation, blurred vision, headaches, tachycardia, and cardiac arrhythmia, which are related to the anticholinergic activity of traditional antiUI drugs, can occur frequently and adversely affect patient compliance. Yet despite the prevalence of unwanted anticholinergic effects in many patients, anticholinergic drugs are currently prescribed for patients having UI. The Merck Manual of Medical Information 631634 (R. Berkow ed., 1997).
About 1 in 10 people develop an ulcer. Ulcers develop as a result of an imbalance between acidsecretory factors, also known as “aggressive factors,” such as stomach acid, pepsin, and Helicobacter pylori infection, and local mucosalprotective factors, such as secretion of bicarbonate, mucus, and prostaglandins.
Treatment of ulcers typically involves reducing or inhibiting the aggressive factors. For example, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach acids. Antacids, however, can cause alkalosis, leading to nausea, headache, and weakness. Antacids can also interfere with the absorption of other drugs into the blood stream and cause diarrhea.
H_{2 }antagonists, such as cimetidine, ranitidine, famotidine, and nizatidine, are also used to treat ulcers. H_{2 }antagonists promote ulcer healing by reducing gastric acid and digestiveenzyme secretion elicited by histamine and other H_{2 }agonists in the stomach and duodenum. H_{2 }antagonists, however, can cause breast enlargement and impotence in men, mental changes (especially in the elderly), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever.
H^{+}, K^{+}ATPase inhibitors such as omeprazole and lansoprazole are also used to treat ulcers. H^{+}, K^{+}ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid. Side effects associated with H^{+}, K^{+}ATPase inhibitors include nausea, diarrhea, abdominal colic, headache, dizziness, somnolence, skin rashes, and transient elevations of plasma activities of aminotransferases.
Sucraflate is also used to treat ulcers. Sucraflate adheres to epithelial cells and is believed to form a protective coating at the base of an ulcer to promote healing. Sucraflate, however, can cause constipation, dry mouth, and interfere with the absorption of other drugs.
Antibiotics are used when Helicobacter pylori is the underlying cause of the ulcer. Often antibiotic therapy is coupled with the administration of bismuth compounds such as bismuth subsalicylate and colloidal bismuth citrate. The bismuth compounds are believed to enhance secretion of mucous and HCO_{3} ^{−}, inhibit pepsin activity, and act as an antibacterial against H. pylori. Ingestion of bismuth compounds, however, can lead to elevated plasma concentrations of Bi^{+3 }and can interfere with the absorption of other drugs.
Prostaglandin analogues, such as misoprostal, inhibit secretion of acid and stimulate the secretion of mucous and bicarbonate and are also used to treat ulcers, especially ulcers in patients who require nonsteroidal antiinflammatory drugs. Effective oral doses of prostaglandin analogues, however, can cause diarrhea and abdominal cramping. In addition, some prostaglandin analogues are abortifacients.
Carbenoxolone, a mineral corticoid, can also be used to treat ulcers. Carbenoxolone appears to alter the composition and quantity of mucous, thereby enhancing the mucosal barrier. Carbenoxolone, however, can lead to Na^{+} and fluid retention, hypertension, hypokalemia, and impaired glucose tolerance.
Muscarinic cholinergic antagonists such as pirenzapine and telenzapine can also be used to reduce acid secretion and treat ulcers. Side effects of muscarinic cholinergic antagonists include dry mouth, blurred vision, and constipation. The Merck Manual of Medical Information 496500 (R. Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis of Therapeutics 901915 (J. Hardman and L. Limbird eds., 9^{th }ed. 1996).
Inflammatorybowel disease (IBD) is a chronic disorder in which the bowel becomes inflamed, often causing recurring abdominal cramps and diarrhea. The two types of IBD are Crohn's disease and ulcerative colitis.
Crohn's disease, which can include regional enteritis, granulomatous ileitis, and ileocolitis, is a chronic inflammation of the intestinal wall. Crohn's disease occurs equally in both sexes and is more common in Jews of easternEuropean ancestry. Most cases of Crohn's disease begin before age 30 and the majority start between the ages of 14 and 24. The disease typically affects the full thickness of the intestinal wall. Generally the disease affects the lowest portion of the small intestine (ileum) and the large intestine, but can occur in any part of the digestive tract.
Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominal pain, fever, loss of appetite, and weight loss. Complications associated with Crohn's disease include the development of intestinal obstructions, abnormal connecting channels (fistulas), and abscesses. The risk of cancer of the large intestine is increased in people who have Crohn's disease. Often Crohn's disease is associated with other disorders such as gallstones, inadequate absorption of nutrients, amyloidosis, arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyoderma gangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primary sclerosing cholangitis. There is no known cure for Crohn's disease.
Cramps and diarrhea, side effects associated with Crohn's disease, can be relieved by anticholinergic drugs, diphenoxylate, loperamide, deodorized opium tincture, or codeine. Generally, the drug is taken orally before a meal.
Broadspectrum antibiotics are often administered to treat the symptoms of Crohn's disease. The antibiotic metronidazole is often administered when the disease affects the large intestine or causes abscesses and fistulas around the anus. Longterm use of metronidazole, however, can damage nerves, resulting in pinsandneedles sensations in the arms and legs. Sulfasalazine and chemically related drugs can suppress mild inflammation, especially in the large intestine. These drugs, however, are less effective in sudden, severe flareups. Corticosteroids, such as prednisone, reduce fever and diarrhea and relieve abdominal pain and tenderness. Longterm corticosteroid therapy, however, invariably results in serious side effects such as high bloodsugar levels, increased risk of infection, osteoporosis, water retention, and fragility of the skin. Drugs such as azathioprine and mercaptourine can compromise the immune system and are often effective for Crohn's disease in patients that do not respond to other drugs. These drugs, however, usually need 3 to 6 months before they produce benefits and can cause serious side effects such as allergy, pancreatitis, and low whitebloodcell count.
When Crohn's disease causes the intestine to be obstructed or when abscesses or fistulas do not heal, surgery can be necessary to remove diseased sections of the intestine. Surgery, however, does not cure the disease, and inflammation tends to recur where the intestine is rejoined. In almost half of the cases a second operation is needed. The Merck Manual of Medical Information 528530 (R. Berkow ed., 1997).
Ulcerative colitis is a chronic disease in which the large intestine becomes inflamed and ulcerated, leading to episodes of bloody diarrhea, abdominal cramps, and fever. Ulcerative colitis usually begins between ages 15 and 30, however, a small group of people have their first attack between ages 50 and 70. Unlike Crohn's disease, ulcerative colitis never affects the small intestine and does not affect the full thickness of the intestine. The disease usually begins in the rectum and the sigmoid colon and eventually spreads partially or completely through out the large intestine. The cause of ulcerative colitis is unknown. Treatment of ulcerative colitis is directed to controlling inflammation, reducing symptoms, and replacing lost fluids and nutrients.
Irritablebowel syndrome (IBS) is a disorder of motility of the entire gastrointestinal tract, causing abdominal pain, constipation, and/or diarrhea. IBS affects threetimes more women than men.
There are two major types of IBS. The first type, spasticcolon type, is commonly triggered by eating, and usually produces periodic constipation and diarrhea with pain. Mucous often appears in the stool. The pain can come in bouts of continuous dull aching pain or cramps, usually in the lower abdomen. The person suffering from spasticcolon type IBS can also experience bloating, gas, nausea, headache, fatigue, depression, anxiety, and difficulty concentrating. The second type of IBS usually produces painless diarrhea or constipation. The diarrhea can begin suddenly and with extreme urgency. Often the diarrhea occurs soon after a meal and can sometimes occur immediately upon awakening.
Treatment of IBS typically involves modification of an IBSpatient's diet. Often it is recommended that an IBS patient avoid beans, cabbage, sorbitol, and fructose. A lowfat, highfiber diet can also help some IBS patients. Regular physical activity can also help keep the gastrointestinal tract functioning properly. Drugs such as propantheline that slow the function of the gastrointestinal tract are generally not effective for treating IBS. Antidiarrheal drugs, such as diphenoxylate and loperamide, help with diarrhea. The Merck Manual of Medical Information 525526 (R. Berkow ed., 1997).
Certain pharmaceutical agents have been administered for treating addiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use of nontoxic NMDAblocking agents coadministered with an addictive substance to prevent the development of tolerance or withdrawal symptoms. U.S. Pat. No. 5,574,052 to Rose et al. discloses coadministration of an addictive substance with an antagonist to partially block the pharmacological effects of the substance. U.S. Pat. No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiate agonist/antagonist to treat cocaine and opiate addiction. U.S. Pat. No. 5,232,934 to Downs discloses administration of 3phenoxypyridine to treat addiction. U.S. Pat. Nos. 5,039,680 and 5,198,459 to Imperato et al. disclose using a serotonin antagonist to treat chemical addiction. U.S. Pat. No. 5,556,837 to Nestler et. al. discloses infusing BDNF or NT4 growth factors to inhibit or reverse neurological adaptive changes that correlate with behavioral changes in an addicted individual. U.S. Pat. No. 5,762,925 to Sagan discloses implanting encapsulated adrenal medullary cells into an animal's central nervous system to inhibit the development of opioid intolerance. U.S. Pat. No. 6,204,284 to Beer et al. discloses racemic (±)1(3,4dichlorophenyl)3azabicyclo[3.1.0]hexane for use in the prevention or relief of a withdrawal syndrome resulting from addiction to drugs and for the treatment of chemical dependencies.
Without treatment, Parkinson's disease progresses to a rigid akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. Drugs commonly used for the treatment of Parkinson's disease include carbidopa/levodopa, pergolide, bromocriptine, selegiline, amantadine, and trihexyphenidyl hydrochloride. There remains, however, a need for drugs useful for the treatment of Parkinson's disease and having an improved therapeutic profile.
Anxiety is a fear, apprehension, or dread of impending danger often accompanied by restlessness, tension, tachycardia, and dyspnea. Currently, benzodiazepines are the most commonly used antianxiety agents for generalized anxiety disorder. Benzodiazepines, however, carry the risk of producing impairment of cognition and skilled motor functions, particularly in the elderly, which can result in confusion, delerium, and falls with fractures. Sedatives are also commonly prescribed for treating anxiety. The azapirones, such as buspirone, are also used to treat moderate anxiety. The azapirones, however, are less useful for treating severe anxiety accompanied with panic attacks.
Epilepsy is a disorder characterized by the tendency to have recurring seizures. Examples of drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital, phenyloin, primidone, valproic acid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γvinyl GABA, acetazolamide, and felbamate. Antiseizure drugs, however, can have side effects such as drowsiness; hyperactivity; hallucinations; inability to concentrate; central and peripheral nervous system toxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingival hyperplasia; gastrointestinal disturbances such as nausea, vomiting, epigastric pain, and anorexia; endocrine effects such as inhibition of antidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; and hypersensitivity such as scarlatiniform rash, morbilliform rash, StevensJohnson syndrome, systemic lupus erythematosus, and hepatic necrosis; and hematological reactions such as redcell aplasia, agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblastic anemia. The Merck Manual of Medical Information 345350 (R. Berkow ed., 1997).
Symptoms of strokes vary depending on what part of the brain is affected. Symptoms include loss or abnormal sensations in an arm or leg or one side of the body, weakness or paralysis of an arm or leg or one side of the body, partial loss of vision or hearing, double vision, dizziness, slurred speech, difficulty in thinking of the appropriate word or saying it, inability to recognize parts of the body, unusual movements, loss of bladder control, imbalance, and falling, and fainting. The symptoms can be permanent and can be associated with coma or stupor. Examples of drugs for treating strokes include anticoagulants such as heparin, drugs that break up clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids. The Merck Manual of Medical Information 352355 (R. Berkow ed., 1997).
Pruritus is an unpleasant sensation that prompts scratching. Conventionally, pruritus is treated by phototherapy with ultraviolet B or PUVA or with therapeutic agents such as naltrexone, nalmefene, danazol, tricyclics, and antidepressants.
Selective antagonists of the metabotropic glutamate receptor 5 (“mGluR5”) have been shown to exert analgesic activity in in vivo animal models (K. Walker et al., Neuropharmacology 40:19 (2000) and A. Dogrul et al., Neuroscience Letters, 292(2):115118 (2000)).
Selective antagonists of the mGluR5 receptor have also been shown to exert anxiolytic and antidepressant activity in in vivo animal models (E. Tatarczynska et al., Br. J. Pharmacol. 132(7):14231430 (2001) and P. J. M. Will et al., Trends in Pharmacological Sciences 22(7):33137 (2001)).
Selective antagonists of the mGluR5 receptor have also been shown to exert antiParkinson activity in vivo (K. J. Ossowska et al., Neuropharmacology 41(4):41320 (2001) and P. J. M. Will et al., Trends in Pharmacological Sciences 22(7):33137 (2001)).
Selective antagonists of the mGluR5 receptor have also been shown to exert antidependence activity in vivo (C. Chiamulera et al., Nature Neuroscience (9):87374 (2001)).
There remains, however, a clear need in the art for new drugs useful for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, amyotrophic lateral sclerosis (“ALS”), dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression.
Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.
The present invention encompasses compounds of formula (I):
Ar_{1 }is
Ar_{2 }is
R_{1 }is —H, halo, —CH_{3}, —CN, —NO_{2}, —OH, —OCH_{3}, —NH_{2}, —C(halo)_{3}, —CH(halo)_{2}, or —CH_{2}(halo);
each R_{2 }is independently:
(a) halo, —OH, —NH_{2}, —CN, or —NO_{2};
(b) —(C_{1}C_{10})alkyl, —(C_{2}C_{10})alkenyl, —(C_{2}C_{10})alkynyl, —(C_{3}C_{10})cycloalkyl, —(C_{8}C_{14})bicycloalkyl, —(C_{8}C_{14})tricycloalkyl, —(C_{5}C_{8})cycloalkenyl, —(C_{8}C_{14})bicycloalkenyl, —(C_{8}C_{14})tricycloalkenyl, (3 to 7membered)heterocycle, or (7 to 10membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R_{5 }groups; or
(c) phenyl, naphthyl, —(C_{14})aryl or (5 to 10membered)heteroaryl, each of which is unsubstituted or substituted with one or more R_{6 }groups;
each R_{3 }is independently:
(a) halo, —OH, —NH_{2}, —CN, or —NO_{2};
(b) —(C_{1}C_{10})alkyl, —(C_{2}C_{10})alkenyl, —(C_{2}C_{10})alkynyl, —(C_{3}C_{10})cycloalkyl, —(C_{8}C_{14})bicycloalkyl, —(C_{8}C_{14})tricycloalkyl, —(C_{5}C_{10})cycloalkenyl, —(C_{8}C_{14})bicycloalkenyl, —(C_{8}C_{14})tricycloalkenyl, (3 to 7membered)heterocycle, or (7 to 10membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R_{5 }groups; or
(c) phenyl, naphthyl, —(C_{14})aryl or (5 to 10membered)heteroaryl, each of which is unsubstituted or substituted with one or more R_{6 }groups;
R_{4 }is —H, —CN, —C(O)O(C_{1}C_{4})alkyl, or —C(O)NH((C_{1}C_{4})alkyl);
each R_{5 }is independently —CN, —OH, —(C_{1}C_{6})alkyl, —(C_{2}C_{6})alkenyl, —(C_{2}C_{6})alkynyl, halo, —N_{3}, —NO_{2}, —N(R_{7})_{2}, —CH═NR_{7}, —NR_{7}OH, —OR_{7}, —COR_{7}, —C(O)OR_{7}, —OC(O)R_{7}, —OC(O)OR_{7}, —SR_{7}, —S(O)R_{7}, or —S(O)_{2}R_{7};
each R_{6 }is independently —(C_{1}C_{6})alkyl, —(C_{2}C_{6})alkenyl, —(C_{2}C_{6})alkynyl, —(C_{3}C_{8})cycloalkyl, —(C_{5}C_{8})cycloalkenyl, phenyl, (3 to 5membered)heterocycle, —C(halo)_{3}, —CH(halo)_{2}, —CH_{2}(halo), —CN, —OH, halo, —N_{3}, —NO_{2}, —N(R_{7})_{2}, —CH═NR_{7}, —NR_{7}OH, —OR_{7}, —COR_{7}, —C(O)OR_{7}, —OC(O)R_{7}, —OC(O)OR_{7}, —SR_{7}, —S(O)R_{7}, or —S(O)_{2}R_{7};
each R_{7 }is independently —H, —(C_{1}C_{6})alkyl, —(C_{2}C_{6})alkenyl, —(C_{2}C_{6})alkynyl, —(C_{3}C_{8})cycloalkyl, —(C_{5}C_{8})cycloalkenyl, phenyl, (3 to 5membered)heterocycle, —C(halo)_{3}, —CH(halo)_{2}, or —CH_{2}(halo);
each R_{8 }is independently —(C_{1}C_{6})alkyl, —(C_{2}C_{6})alkenyl, —(C_{2}C_{6})alkynyl, —(C_{3}C_{8})cycloalkyl, —(C_{5}C_{8})cycloalkenyl, phenyl, (3 to 5membered)heterocycle, —C(halo)_{3}, —CH(halo)_{2}, —CH_{2}(halo), —CN, —OH, halo, —N_{3}, —NO_{2}, —N(R_{7})_{2}, —CH═NR_{7}, —NR_{7}OH, —OR_{7}, —COR_{7}, —C(O)OR_{7}, —OC(O)R_{7}, —OC(O)OR_{7}, —SR_{7}, —S(O)R_{7}, or —S(O)_{2}R_{7};
each halo is independently —F, —Cl, —Br, or —I;
m is an integer ranging from 0 to 2;
n is an integer ranging from 0 to 3;
p is an integer ranging from 0 to 2;
q is an integer ranging from 0 to 6;
r is an integer ranging from 0 to 5; and
s is an integer ranging from 0 to 4.
The invention further encompasses compounds of formula (II):
Ar_{1 }is
R_{1 }is —H, halo, —CH_{3}, —CN, —NO_{2}, —OH, —OCH_{3}, —NH_{2}, —C(halo)_{3}, —CH(halo)_{2}, or —CH_{2}(halo);
each R_{2 }is independently:
(a) halo, —OH, —NH_{2}, —CN, or —NO_{2};
(b) —(C_{1}C_{10})alkyl, —(C_{2}C_{10})alkenyl, —(C_{2}C_{10})alkynyl, —(C_{3}C_{10})cycloalkyl, —(C_{8}C_{14})bicycloalkyl, —(C_{8}C_{4})tricycloalkyl, —(C_{5}C_{8})cycloalkenyl, —(C_{8}C_{14})bicycloalkenyl, —(C_{8}C_{14})tricycloalkenyl, (3 to 7membered)heterocycle, or (7 to 10membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R_{5 }groups; or
(c) phenyl, naphthyl, —(C_{14})aryl or (5 to 10membered)heteroaryl, each of which is unsubstituted or substituted with one or more R_{6 }groups;
each R_{3 }is independently:
(a) halo, —OH, —NH_{2}, —CN, or —NO_{2};
(b) —(C_{1}C_{10})alkyl, —(C_{2}C_{10})alkenyl, —(C_{2}C_{10})alkynyl, —(C_{3}C_{10})cycloalkyl, —(C_{8}C_{14})bicycloalkyl, —(C_{8}C_{14})tricycloalkyl, —(C_{5}C_{10})cycloalkenyl, —(C_{8}C_{14})bicycloalkenyl, —(C_{8}C_{14})tricycloalkenyl, (3 to 7membered)heterocycle, or (7 to 10membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R_{5 }groups; or
(c) phenyl, naphthyl, —(C_{14})aryl or (5 to 10membered)heteroaryl, each of which is unsubstituted or substituted with one or more R_{6 }groups;
R_{4 }is —H, —CN, —C(O)O(C_{1}C_{4})alkyl, or —C(O)NH((C_{1}C_{4})alkyl);
each R_{5 }is independently —CN, —OH, —(C_{1}C_{6})alkyl, —(C_{2}C_{6})alkenyl, —(C_{2}C_{6})alkynyl, halo, —N_{3}, —NO_{2}, —N(R_{7})_{2}, —CH═NR_{7}, —NR_{7}OH, —OR_{7}, —COR_{7}, —C(O)OR_{7}, —OC(O)R_{7}, —OC(O)OR_{7}, —SR_{7}, —S(O)R_{7}, or —S(O)_{2}R_{7};
each R_{6 }is independently —(C_{1}C_{6})alkyl, —(C_{2}C_{6})alkenyl, —(C_{2}C_{6})alkynyl, —(C_{3}C_{8})cycloalkyl, —(C_{5}C_{8})cycloalkenyl, phenyl, (3 to 5membered)heterocycle, —C(halo)_{3}, —CH(halo)_{2}, —CH_{2}(halo), —CN, —OH, halo, —N_{3}, —NO_{2}, —N(R_{7})_{2}, —CH═NR_{7}, —NR_{7}OH, —OR_{7}, —COR_{7}, —C(O)OR_{7}, —OC(O)R_{7}, —OC(O)OR_{7}, —SR_{7}, —S(O)R_{7}, or —S(O)_{2}R_{7};
each R_{7 }is independently —H, —(C_{1}C_{6})alkyl, —(C_{2}C_{6})alkenyl, —(C_{2}C_{6})alkynyl, —(C_{3}C_{8})cycloalkyl, —(C_{5}C_{8})cycloalkenyl, phenyl, (3 to 5membered)heterocycle, —C(halo)_{3}, —CH(halo)_{2}, or —CH_{2}(halo);
each R_{9 }is independently —(C_{1}C_{6})alkyl, —(C_{2}C_{6})alkenyl, —(C_{2}C_{6})alkynyl, —(C_{3}C_{8})cycloalkyl, —(C_{5}C_{8})cycloalkenyl, phenyl, (3 to 5membered)heterocycle, —C(halo)_{3}, —CH(halo)_{2}, —CH_{2}(halo), —CN, —OH, halo, —N_{3}, —NO_{2}, —N(R_{7})_{2}, —CH═NR_{7}, —NR_{7}OH, —OR_{7}, —COR_{7}, —C(O)OR_{7}, —OC(O)R_{7}, —OC(O)OR_{7}, —SR_{7}, —S(O)R_{7}, or —S(O)_{2}R_{7};
each halo is independently —F, —Cl, —Br, or —I;
m is an integer ranging from 0 to 2;
n is an integer ranging from 0 to 3;
p is an integer ranging from 0 to 2;
q is an integer ranging from 0 to 6;
r is an integer ranging from 0 to 5; and
s is an integer ranging from 0 to 4.
A compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof (a “Nitro(cyano)vinylpiperazine Compound”) is useful for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression (each being a “Condition”) in an animal.
The invention also relates to compositions comprising an effective amount of a Nitro(cyano)vinylpiperazine Compound and a pharmaceutically acceptable vehicle. The compositions are useful for treating or preventing a Condition in an animal.
The invention further relates to methods for treating a Condition, comprising administering to an animal in need thereof an effective amount of a Nitro(cyano)vinylpiperazine Compound.
The invention further relates to methods for preventing a Condition, comprising administering to an animal in need thereof an effective amount of a Nitro(cyano)vinylpiperazine Compound.
The invention still further relates to methods for inhibiting Vanilloid Receptor 1 (“VR1”) function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of a Nitro(cyano)vinylpiperazine Compound.
The invention still further relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Nitro(cyano)vinylpiperazine Compound.
The invention still further relates to methods for inhibiting metabotropic glutamate receptor 1 (“mGluR1”) function in a cell, comprising contacting a cell capable of expressing mGluR1 with an effective amount of a Nitro(cyano)vinylpiperazine Compound.
The invention still further relates to methods for preparing a composition, comprising the step of admixing a Nitro(cyano)vinylpiperazine Compound and a pharmaceutically acceptable carrier or excipient.
The invention still further relates to a kit comprising a container containing an effective amount of a Nitro(cyano)vinylpiperazine Compound.
The present invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify nonlimiting embodiments of the invention.
As stated above, the present invention encompasses Nitro(cyano)vinylpiperazine Compounds of formula (I)
In one embodiment, Ar_{1 }is a pyridyl group.
In another embodiment Ar_{1 }is a pyrimidinyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group.
In another embodiment, Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, m is 0.
In another embodiment, m is 1.
In another embodiment, m is 2.
In another embodiment, n is 0.
In another embodiment, n is 1.
In another embodiment, n is 2.
In another embodiment, n is 3.
In another embodiment, p is 0.
In another embodiment, p is 1.
In another embodiment, p is 2.
In another embodiment, r is 0.
In another embodiment, r is 1.
In another embodiment, r is 2.
In another embodiment, r is 3.
In another embodiment, r is 4.
In another embodiment, r is 5.
In another embodiment, q is 0.
In another embodiment, q is 1.
In another embodiment, q is 2.
In another embodiment, q is 3.
In another embodiment, q is 4.
In another embodiment, q is 5.
In another embodiment, q is 6.
In another embodiment, s is 0.
In another embodiment, s is 1.
In another embodiment, s is 2.
In another embodiment, s is 3.
In another embodiment, s is 4.
In another embodiment, R_{1 }is —H.
In another embodiment, R_{1 }is halo.
In another embodiment, R_{1 }is —Cl.
In another embodiment, R_{1 }is —Br.
In another embodiment, R_{1 }is —I.
In another embodiment, R_{1 }is —F.
In another embodiment, R_{1 }is —CH_{3}.
In another embodiment, R_{1 }is —CN.
In another embodiment, R_{1 }is —NO_{2}.
In another embodiment, R_{1 }is —OH.
In another embodiment, R_{1 }is —OCH_{3}.
In another embodiment, R_{1 }is —NH_{2}.
In another embodiment, R_{1 }is —C(halo)_{3}.
In another embodiment, R_{1 }is —CH(halo)_{2}.
In another embodiment, R_{1 }is —CH_{2}(halo).
In another embodiment, R_{1 }is —CF_{3}.
In another embodiment, n or p is 1 and R_{2 }is halo, —OH, —NH_{2}, —CN, or —NO_{2}.
In another embodiment, n or p is 1 and R_{2 }is —(C_{1}C_{10})alkyl, —(C_{2}C_{10})alkenyl, —(C_{2}C_{10})alkynyl, —(C_{3}C_{10})cycloalkyl, —(C_{8}C_{14})bicycloalkyl, —(C_{8}C_{14})tricycloalkyl, —(C_{5}C_{8})cycloalkenyl, —(C_{8}C_{14})bicycloalkenyl, —(C_{8}C_{14})tricycloalkenyl, (3 to 7membered)heterocycle, or (7 to 10membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R_{5 }groups.
In another embodiment, n or p is 1 and R_{2 }is phenyl, naphthyl, —(C_{14})aryl or (5 to 10membered)heteroaryl, each of which is unsubstituted or substituted with one or more R_{6 }groups.
In another embodiment, m is 1 and R_{3 }is halo, —OH, —NH_{2}, —CN, or —NO_{2};
In another embodiment, m is 1 and R_{3 }is —(C_{1}C_{10})alkyl, —(C_{2}C_{10})alkenyl, —(C_{2}C_{10})alkynyl, —(C_{3}C_{10})cycloalkyl, —(C_{8}C_{14})bicycloalkyl, —(C_{8}C_{14})tricycloalkyl, —(C_{5}C_{10})cycloalkenyl, —(C_{8}C_{14})bicycloalkenyl, —(C_{8}C_{14})tricycloalkenyl, (3 to 7membered)heterocycle, or (7 to 10membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R_{5 }groups.
In another embodiment, m is 1 and R_{3 }is phenyl, naphthyl, —(C_{14})aryl or (5 to 10membered)heteroaryl, each of which is unsubstituted or substituted with one or more R_{6 }groups.
In another embodiment, m is 1 and R_{3 }is —(C_{1}C_{10})alkyl.
In another embodiment, m is 1, R_{3 }is —(C_{1}C_{10})alkyl, and the carbon atom to which the R_{3 }group is attached is in the (R) configuration.
In another embodiment, m is 1, R_{3 }is —(C_{1}C_{10})alkyl, and the carbon atom to which the R_{3 }group is attached is in the (S) configuration.
In another embodiment, m is 1 and R_{3 }is —CH_{3}.
In another embodiment, m is 1, R_{3 }is —CH_{3}, and the carbon atom to which the R_{3 }group is attached is in the (R) configuration.
In another embodiment, m is 1, R_{3 }is —CH_{3}, and the carbon atom to which the R_{3 }group is attached is in the (S) configuration.
In another embodiment, m is 1 and R_{3 }is halo.
In another embodiment, m is 1 and R_{3 }is —Cl.
In another embodiment, m is 1 and R_{3 }is —Br.
In another embodiment, m is 1 and R_{3 }is —I.
In another embodiment, m is 1 and R_{3 }is —F.
In another embodiment, R_{4 }is —H.
In another embodiment, R_{4 }is —CN.
In another embodiment, R_{4 }is —C(O)O(C_{1}C_{4})alkyl.
In another embodiment, R_{2 }is or —C(O)NH((C_{1}C_{4})alkyl).
In another embodiment, Ar_{2 }is a benzothiazolyl group and s is 1.
In another embodiment, Ar_{2 }is a benzoimidazolyl group and s is 1.
In another embodiment, Ar_{2 }is a benzooxazolyl group and s is 1.
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 1, R_{3 }is —CH, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
The present invention further encompasses Nitro(cyano)vinylpiperazine Compounds of formula (II)
In one embodiment, Ar_{1 }is a pyridyl group.
In another embodiment Ar_{1 }is a pyrimidinyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group.
In another embodiment, Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, m is 0.
In another embodiment, m is 1.
In another embodiment, m is 2.
In another embodiment, n is 0.
In another embodiment, n is 1.
In another embodiment, n is 2.
In another embodiment, n is 3.
In another embodiment, p is 0.
In another embodiment, p is 1.
In another embodiment, p is 2.
In another embodiment, r is 0.
In another embodiment, r is 1.
In another embodiment, r is 2.
In another embodiment, r is 3.
In another embodiment, r is 4.
In another embodiment, r is 5.
In another embodiment, q is 0.
In another embodiment, q is 1.
In another embodiment, q is 2.
In another embodiment, q is 3.
In another embodiment, q is 4.
In another embodiment, q is 5.
In another embodiment, q is 6.
In another embodiment, s is 0.
In another embodiment, s is 1.
In another embodiment, s is 2.
In another embodiment, s is 3.
In another embodiment, s is 4.
In another embodiment, R_{1 }is —H.
In another embodiment, R_{1 }is halo.
In another embodiment, R_{1 }is —Cl.
In another embodiment, R_{1 }is —Br.
In another embodiment, R_{1 }is —I.
In another embodiment, R_{1 }is —F.
In another embodiment, R_{1 }is —CH_{3}.
In another embodiment, R_{1 }is —CN.
In another embodiment, R_{1 }is —NO_{2}.
In another embodiment, R_{1 }is —OH.
In another embodiment, R_{1 }is —OCH_{3}.
In another embodiment, R_{1 }is —NH_{2}.
In another embodiment, R_{1 }is —CH(halo)_{3}.
In another embodiment, R_{1 }is —CH(halo)_{2}.
In another embodiment, R_{1 }is —CH_{2}(halo).
In another embodiment, R_{1 }is —CF_{3}.
In another embodiment, n or p is 1 and R_{2 }is halo, —OH, —NH_{2}, —CN, or —NO_{2}.
In another embodiment, n or p is 1 and R_{2 }is —(C_{1}C_{10})alkyl, —(C_{2}C_{10})alkenyl, —(C_{2}C_{10})alkynyl, —(C_{3}C_{10})cycloalkyl, —(C_{8}C_{14})bicycloalkyl, —(C_{8}C_{14})tricycloalkyl, —(C_{5}C_{8})cycloalkenyl, —(C_{8}C_{14})bicycloalkenyl, —(C_{8}C_{14})tricycloalkenyl, (3 to 7membered)heterocycle, or (7 to 10membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R_{5 }groups.
In another embodiment, n or p is 1 and R_{2 }is phenyl, naphthyl, —(C_{14})aryl or (5 to 10membered)heteroaryl, each of which is unsubstituted or substituted with one or more R_{6 }groups.
In another embodiment, m is 1 and R_{3 }is halo, —OH, —NH_{2}, —CN, or —NO_{2};
In another embodiment, m is 1 and R_{3 }is —(C_{1}C_{10})alkyl, —(C_{2}C_{10})alkenyl, —(C_{2}C_{10})alkynyl, —(C_{3}C_{10})cycloalkyl, —(C_{8}C_{14})bicycloalkyl, —(C_{8}C_{14})tricycloalkyl, —(C_{5}C_{10})cycloalkenyl, —(C_{8}C_{14})bicycloalkenyl, —(C_{8}C_{14})tricycloalkenyl, (3 to 7membered)heterocycle, or (7 to 10membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R_{5 }groups.
In another embodiment, m is 1 and R_{3 }is phenyl, naphthyl, —(C_{14})aryl or (5 to 10membered)heteroaryl, each of which is unsubstituted or substituted with one or more R_{6 }groups.
In another embodiment, m is 1 and R_{3 }is —(C_{1}C_{10})alkyl.
In another embodiment, m is 1, R_{3 }is —(C_{1}C_{10})alkyl, and the carbon atom to which the R_{3 }group is attached is in the (R) configuration.
In another embodiment, m is 1, R_{3 }is —(C_{1}C_{10})alkyl, and the carbon atom to which the R_{3 }group is attached is in the (S) configuration.
In another embodiment, m is 1 and R_{3 }is —CH_{3}.
In another embodiment, m is 1, R_{3 }is —CH_{3}, and the carbon atom to which the R_{3 }group is attached is in the (R) configuration.
In another embodiment, m is 1, R_{3 }is —CH_{3}, and the carbon atom to which the R_{3 }group is attached is in the (S) configuration.
In another embodiment, m is 1 and R_{3 }is halo.
In another embodiment, m is 1 and R_{3 }is —Cl.
In another embodiment, m is 1 and R_{3 }is —Br.
In another embodiment, m is 1 and R_{3 }is —I.
In another embodiment, m is 1 and R_{3 }is —F.
In another embodiment, R_{4 }is —H.
In another embodiment, R_{4 }is —CN.
In another embodiment, R_{4 }is —C(O)O(C_{1}C_{4})alkyl.
In another embodiment, R_{4 }is or —C(O)NH((C_{1}C_{4})alkyl).
In another embodiment, Ar_{2 }is a benzothiazolyl group and s is 1.
In another embodiment, Ar_{2 }is a benzoimidazolyl group and s is 1.
In another embodiment, Ar_{2 }is a benzooxazolyl group and s is 1.
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 0, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 0, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyrimidinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a pyridazinyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzothiazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzooxazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is a benzoimidazolyl group.
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, m is 1, R_{3 }is —CH_{3}, and Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
In another embodiment, Ar_{1 }is a thiadiazolyl group, r is 1, m is 1, R_{3 }is —CH_{3}, Ar_{2 }is
Certain Nitro(cyano)vinylpiperazine Compounds can have asymmetric centers and therefore exist in different enantiomeric and diastereomic forms. This invention relates to the use of all optical isomers and stereoisomers of the Nitro(cyano)vinylpiperazine Compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
The Nitro(cyano)vinylpiperazine Compounds have a double bond to which is bonded an R_{4 }group and AR_{2}—NH— group, each of which can be cis or trans relative to the other. Accordingly, the present invention encompasses Nitro(cyano)vinylpiperazine Compounds in which the R_{4 }group and the Ar_{2}—NH— group are cis relative to each other, Nitro(cyano)vinylpiperazine Compounds in which the R_{4 }group and the Ar_{2}—NH— group are trans relative to each other, and all mixtures thereof. Formula (I) and (II) are intended to encompass: (i) Nitro(cyano)vinylpiperazine Compounds in which the R_{4 }group and the Ar_{2}—NH— group are trans relative to each other, (ii) Nitro(cyano)vinylpiperazine Compounds in which the R_{4 }group and the Ar_{2}—NH— group are cis relative to each other, and (iii) all mixtures thereof.
In the Nitro(cyano)vinylpiperazine Compounds each R_{3 }can be attached to any carbon of the piperazine ring. In one embodiment, the Nitro(cyano)vinylpiperazine Compounds have only one R_{3 }group, i.e., m=1, and that R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, and that R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group.
In another embodiment, two R_{3 }groups are attached to a single carbon atom of the piperazine ring. In another embodiment, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group and another R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group.
In another embodiment, the Nitro(cyano)vinylpiperazine Compound has two R_{3 }groups, i.e., m=2, each being attached to a different carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has two R_{3 }groups, each being attached to a different carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group.
In one embodiment, where the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, a carbon atom to which an R_{3 }group is attached has the (R) configuration. In another embodiment, where the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, a carbon atom to which the R_{3 }group is attached has the (S) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, and at least one of the carbon atoms to which an R_{3 }group is attached has the (R) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, and at least one of the carbon atoms to which an R_{3 }group is attached has the (S) configuration.
In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R_{3 }group is attached is in the (R) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —(C_{1}C_{4})alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CH_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CF_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CH_{2}CH_{3}.
In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, and the carbon to which the R_{3 }group is attached is in the (R) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —(C_{1}C_{4})alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CH_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CF_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CH_{2}CH_{3}.
In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R_{3 }group is attached is in the (S) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —(C_{1}C_{4})alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CH_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CF_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CH_{2}CH_{3}.
In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, and the carbon to which the R_{3 }group is attached is in the (S) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —(C_{1}C_{4})alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CH_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CF_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has one or two R_{3 }groups, an R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CH_{2}CH_{3}.
In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R_{3 }group is attached is in the (R) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —(C_{1}C_{4})alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CH_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CF_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CH_{2}CH_{3}.
In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, and the carbon to which the R_{3 }group is attached is in the (R) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —(C_{1}C_{4})alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CH_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CF_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CH_{2}CH_{3}.
In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R_{3 }group is attached is in the (S) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —(C_{1}C_{4})alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CH_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CF_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CH_{2}CH_{3}.
In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, and the carbon to which the R_{3 }group is attached is in the (S) configuration. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —(C_{1}C_{4})alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CH_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (S) configuration, and R_{3 }is —CF_{3}. In another embodiment, the Nitro(cyano)vinylpiperazine Compound has only one R_{3 }group, the R_{3 }group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(NHAr_{2})═C(CN)(R_{4}) group or —C(NHAr_{2})═C(NO_{2})(R_{4}) group, the carbon to which the R_{3 }group is attached is in the (R) configuration, and R_{3 }is —CH_{2}CH_{3}.
The bonds represented by a
line in the Nitro(cyano)vinylpiperazine compounds of Formula (I) and Formula (II) mean that the R_{4 }group and the Ar_{2}—NH— group can be cis relative to each other, trans relative to each other, or a mixture of the cis and transisomers.Illustrative Nitro(cyano)vinylpiperazine Compounds are listed below in Tables 17.
For the chemical structure depicted, e.g., at the head of each of Tables 17, a is independently 0 or 1. When a=0, the group at the “a” position is —H. When a=1, the group at the “a” position (R_{8a}) is other than —H, i.e., is R_{8}.
TABLE 1  
(III)  


and pharmaceutically acceptable salts thereof, where:  
Compound  Ar_{1}  R_{8a}  
A1 (a, b, c, and d)  2(3chloropyridyl)  tertbutyl  
A2 (a, b, c, and d)  2(3chloropyridyl)  isobutyl  
A3 (a, b, c, and d)  2(3chloropyridyl)  secbutyl  
A4 (a, b, c, and d)  2(3chloropyridyl)  cyclohexyl  
A5 (a, b, c, and d)  2(3chloropyridyl)  tertbutoxy  
A6 (a, b, c, and d)  2(3chloropyridyl)  isopropoxy  
A7 (a, b, c, and d)  2(3chloropyridyl)  —CF_{3}  
A8 (a, b, c, and d)  2(3chloropyridyl)  —OCF_{3}  
A9 (a, b, c, and d)  2(3chloropyridyl)  —Cl  
A10 (a, b, c, and d)  2(3chloropyridyl)  —Br  
A11 (a, b, c, and d)  2(3chloropyridyl)  —I  
A12 (a, b, c, and d)  2(3chloropyridyl)  nbutyl  
A13 (a, b, c, and d)  2(3chloropyridyl)  npropyl  
A14 (a, b, c, and d)  2(3chloropyridyl)  isopropyl  
A15 (a, b, c, and d)  2(3fluoropyridyl)  tertbutyl  
A16 (a, b, c, and d)  2(3fluoropyridyl)  isobutyl  
A17 (a, b, c, and d)  2(3fluoropyridyl)  secbutyl  
A18 (a, b, c, and d)  2(3fluoropyridyl)  cyclohexyl  
A19 (a, b, c, and d)  2(3fluoropyridyl)  tertbutoxy  
A20 (a, b, c, and d)  2(3fluoropyridyl)  isopropoxy  
A21 (a, b, c, and d)  2(3fluoropyridyl)  —CF_{3}  
A22 (a, b, c, and d)  2(3fluoropyridyl)  —OCF_{3}  
A23 (a, b, c, and d)  2(3fluoropyridyl)  —Cl  
A24 (a, b, c, and d)  2(3fluoropyridyl)  —Br  
A25 (a, b, c, and d)  2(3fluoropyridyl)  —I  
A26 (a, b, c, and d)  2(3fluoropyridyl)  nbutyl  
A27 (a, b, c, and d)  2(3fluoropyridyl)  npropyl  
A28 (a, b, c, and d)  2(3fluoropyridyl)  isopropyl  
A29 (a, b, c, and d)  2(3methylpyridyl)  tertbutyl  
A30 (a, b, c, and d)  2(3methylpyridyl)  isobutyl  
A31 (a, b, c, and d)  2(3methylpyridyl)  secbutyl  
A32 (a, b, c, and d)  2(3methylpyridyl)  cyclohexyl  
A33 (a, b, c, and d)  2(3methylpyridyl)  tertbutoxy  
A34 (a, b, c, and d)  2(3methylpyridyl)  isopropoxy  
A35 (a, b, c, and d)  2(3methylpyridyl)  —CF_{3}  
A36 (a, b, c, and d)  2(3methylpyridyl)  —OCF_{3}  
A37 (a, b, c, and d)  2(3methylpyridyl)  —Cl  
A38 (a, b, c, and d)  2(3methylpyridyl)  —Br  
A39 (a, b, c, and d)  2(3methylpyridyl)  —I  
A40 (a, b, c, and d)  2(3methylpyridyl)  nbutyl  
A41 (a, b, c, and d)  2(3methylpyridyl)  npropyl  
A42 (a, b, c, and d)  2(3methylpyridyl)  isopropyl  
A43 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutyl  
A44 (a, b, c, and d)  2(3CF_{3}pyridyl)  isobutyl  
A45 (a, b, c, and d)  2(3CF_{3}pyridyl)  secbutyl  
A46 (a, b, c, and d)  2(3CF_{3}pyridyl)  cyclohexyl  
A47 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutoxy  
A48 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropoxy  
A49 (a, b, c, and d)  2(3CF_{3}pyridyl)  —CF_{3}  
A50 (a, b, c, and d)  2(3CF_{3}pyridyl)  —OCF_{3}  
A51 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Cl  
A52 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Br  
A53 (a, b, c, and d)  2(3CF_{3}pyridyl)  —I  
A54 (a, b, c, and d)  2(3CF_{3}pyridyl)  nbutyl  
A55 (a, b, c, and d)  2(3CF_{3}pyridyl)  npropyl  
A56 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropyl  
A57 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutyl  
A58 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isobutyl  
A59 (a, b, c, and d)  2(3CHF_{2}pyridyl)  secbutyl  
A60 (a, b, c, and d)  2(3CHF_{2}pyridyl)  cyclohexyl  
A61 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutoxy  
A62 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropoxy  
A63 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —CF_{3}  
A64 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —OCF_{3}  
A65 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Cl  
A66 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Br  
A67 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —I  
A68 (a, b, c, and d)  2(3CHF_{2}pyridyl)  nbutyl  
A69 (a, b, c, and d)  2(3CHF_{2}pyridyl)  npropyl  
A70 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropyl  
A71 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutyl  
A72 (a, b, c, and d)  2(3hydroxypyridyl)  isobutyl  
A73 (a, b, c, and d)  2(3hydroxypyridyl)  secbutyl  
A74 (a, b, c, and d)  2(3hydroxypyridyl)  cyclohexyl  
A75 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutoxy  
A76 (a, b, c, and d)  2(3hydroxypyridyl)  isopropoxy  
A77 (a, b, c, and d)  2(3hydroxypyridyl)  —CF_{3}  
A78 (a, b, c, and d)  2(3hydroxypyridyl)  —OCF_{3}  
A79 (a, b, c, and d)  2(3hydroxypyridyl)  —Cl  
A80 (a, b, c, and d)  2(3hydroxypyridyl)  —Br  
A81 (a, b, c, and d)  2(3hydroxypyridyl)  —I  
A82 (a, b, c, and d)  2(3hydroxypyridyl)  nbutyl  
A83 (a, b, c, and d)  2(3hydroxypyridyl)  npropyl  
A84 (a, b, c, and d)  2(3hydroxypyridyl)  isopropyl  
A85 (a, b, c, and d)  2(3nitropyridyl)  tertbutyl  
A86 (a, b, c, and d)  2(3nitropyridyl)  isobutyl  
A87 (a, b, c, and d)  2(3nitropyridyl)  secbutyl  
A88 (a, b, c, and d)  2(3nitropyridyl)  cyclohexyl  
A89 (a, b, c, and d)  2(3nitropyridyl)  tertbutoxy  
A90 (a, b, c, and d)  2(3nitropyridyl)  isopropoxy  
A91 (a, b, c, and d)  2(3nitropyridyl)  —CF_{3}  
A92 (a, b, c, and d)  2(3nitropyridyl)  —OCF_{3}  
A93 (a, b, c, and d)  2(3nitropyridyl)  —Cl  
A94 (a, b, c, and d)  2(3nitropyridyl)  —Br  
A95 (a, b, c, and d)  2(3nitropyridyl)  —I  
A96 (a, b, c, and d)  2(3nitropyridyl)  nbutyl  
A97 (a, b, c, and d)  2(3nitropyridyl)  npropyl  
A98 (a, b, c, and d)  2(3nitropyridyl)  isopropyl  
A99 (a, b, c, and d)  2(3cyanopyridyl)  tertbutyl  
A100 (a, b, c, and d)  2(3cyanopyridyl)  isobutyl  
A101 (a, b, c, and d)  2(3cyanopyridyl)  secbutyl  
A102 (a, b, c, and d)  2(3cyanopyridyl)  cyclohexyl  
A103 (a, b, c, and d)  2(3cyanopyridyl)  tertbutoxy  
A104 (a, b, c, and d)  2(3cyanopyridyl)  isopropoxy  
A105 (a, b, c, and d)  2(3cyanopyridyl)  —CF_{3}  
A106 (a, b, c, and d)  2(3cyanopyridyl)  —OCF_{3}  
A107 (a, b, c, and d)  2(3cyanopyridyl)  —Cl  
A108 (a, b, c, and d)  2(3cyanopyridyl)  —Br  
A109 (a, b, c, and d)  2(3cyanopyridyl)  —I  
A110 (a, b, c, and d)  2(3cyanopyridyl)  nbutyl  
A111 (a, b, c, and d)  2(3cyanopyridyl)  npropyl  
A112 (a, b, c, and d)  2(3cyanopyridyl)  isopropyl  
A113 (a, b, c, and d)  2(3bromopyridyl)  tertbutyl  
A114 (a, b, c, and d)  2(3bromopyridyl)  isobutyl  
A115 (a, b, c, and d)  2(3bromopyridyl)  secbutyl  
A116 (a, b, c, and d)  2(3bromopyridyl)  cyclohexyl  
A117 (a, b, c, and d)  2(3bromopyridyl)  tertbutoxy  
A118 (a, b, c, and d)  2(3bromopyridyl)  isopropoxy  
A119 (a, b, c, and d)  2(3bromopyridyl)  —CF_{3}  
A120 (a, b, c, and d)  2(3bromopyridyl)  —OCF_{3}  
A121 (a, b, c, and d)  2(3bromopyridyl)  —Cl  
A122 (a, b, c, and d)  2(3bromopyridyl)  —Br  
A123 (a, b, c, and d)  2(3bromopyridyl)  —I  
A124 (a, b, c, and d)  2(3bromopyridyl)  nbutyl  
A125 (a, b, c, and d)  2(3bromopyridyl)  npropyl  
A126 (a, b, c, and d)  2(3bromopyridyl)  isopropyl  
A127 (a, b, c, and d)  2(3iodopyridyl)  tertbutyl  
A128 (a, b, c, and d)  2(3iodopyridyl)  isobutyl  
A129 (a, b, c, and d)  2(3iodopyridyl)  secbutyl  
A130 (a, b, c, and d)  2(3iodopyridyl)  cyclohexyl  
A131 (a, b, c, and d)  2(3iodopyridyl)  tertbutoxy  
A132 (a, b, c, and d)  2(3iodopyridyl)  isopropoxy  
A133 (a, b, c, and d)  2(3iodopyridyl)  —CF_{3}  
A134 (a, b, c, and d)  2(3iodopyridyl)  —OCF_{3}  
A135 (a, b, c, and d)  2(3iodopyridyl)  —Cl  
A136 (a, b, c, and d)  2(3iodopyridyl)  —Br  
A137 (a, b, c, and d)  2(3iodopyridyl)  —I  
A138 (a, b, c, and d)  2(3iodopyridyl)  nbutyl  
A139 (a, b, c, and d)  2(3iodopyridyl)  npropyl  
A140 (a, b, c, and d)  2(3iodopyridyl)  isopropyl  
A141 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutyl  
A142 (a, b, c, and d)  4(5chloropyrimidinyl)  isobutyl  
A143 (a, b, c, and d)  4(5chloropyrimidinyl)  secbutyl  
A144 (a, b, c, and d)  4(5chloropyrimidinyl)  cyclohexyl  
A145 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutoxy  
A146 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropoxy  
A147 (a, b, c, and d)  4(5chloropyrimidinyl)  —CF_{3}  
A148 (a, b, c, and d)  4(5chloropyrimidinyl)  —OCF_{3}  
A149 (a, b, c, and d)  4(5chloropyrimidinyl)  —Cl  
A150 (a, b, c, and d)  4(5chloropyrimidinyl)  —Br  
A151 (a, b, c, and d)  4(5chloropyrimidinyl)  —I  
A152 (a, b, c, and d)  4(5chloropyrimidinyl)  nbutyl  
A153 (a, b, c, and d)  4(5chloropyrimidinyl)  npropyl  
A154 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropyl  
A155 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutyl  
A156 (a, b, c, and d)  4(5methylpyrimidinyl)  isobutyl  
A157 (a, b, c, and d)  4(5methylpyrimidinyl)  secbutyl  
A158 (a, b, c, and d)  4(5methylpyrimidinyl)  cyclohexyl  
A159 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutoxy  
A160 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropoxy  
A161 (a, b, c, and d)  4(5methylpyrimidinyl)  —CF_{3}  
A162 (a, b, c, and d)  4(5methylpyrimidinyl)  —OCF_{3}  
A163 (a, b, c, and d)  4(5methylpyrimidinyl)  —Cl  
A164 (a, b, c, and d)  4(5methylpyrimidinyl)  —Br  
A165 (a, b, c, and d)  4(5methylpyrimidinyl)  —I  
A166 (a, b, c, and d)  4(5methylpyrimidinyl)  nbutyl  
A167 (a, b, c, and d)  4(5methylpyrimidinyl)  npropyl  
A168 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropyl  
A169 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutyl  
A170 (a, b, c, and d)  4(5fluoropyrimidinyl)  isobutyl  
A171 (a, b, c, and d)  4(5fluoropyrimidinyl)  secbutyl  
A172 (a, b, c, and d)  4(5fluoropyrimidinyl)  cyclohexyl  
A173 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutoxy  
A174 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropoxy  
A175 (a, b, c, and d)  4(5fluoropyrimidinyl)  —CF_{3}  
A176 (a, b, c, and d)  4(5fluoropyrimidinyl)  —OCF_{3}  
A177 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Cl  
A178 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Br  
A179 (a, b, c, and d)  4(5fluoropyrimidinyl)  —I  
A180 (a, b, c, and d)  4(5fluoropyrimidinyl)  nbutyl  
A181 (a, b, c, and d)  4(5fluoropyrimidinyl)  npropyl  
A182 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropyl  
A183 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutyl  
A184 (a, b, c, and d)  2(3chloropyrazinyl)  isobutyl  
A185 (a, b, c, and d)  2(3chloropyrazinyl)  secbutyl  
A186 (a, b, c, and d)  2(3chloropyrazinyl)  cyclohexyl  
A187 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutoxy  
A188 (a, b, c, and d)  2(3chloropyrazinyl)  isopropoxy  
A189 (a, b, c, and d)  2(3chloropyrazinyl)  —CF_{3}  
A190 (a, b, c, and d)  2(3chloropyrazinyl)  —OCF_{3}  
A191 (a, b, c, and d)  2(3chloropyrazinyl)  —Cl  
A192 (a, b, c, and d)  2(3chloropyrazinyl)  —Br  
A193 (a, b, c, and d)  2(3chloropyrazinyl)  —I  
A194 (a, b, c, and d)  2(3chloropyrazinyl)  nbutyl  
A195 (a, b, c, and d)  2(3chloropyrazinyl)  npropyl  
A196 (a, b, c, and d)  2(3chloropyrazinyl)  isopropyl  
A197 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutyl  
A198 (a, b, c, and d)  2(3methylpyrazinyl)  isobutyl  
A199 (a, b, c, and d)  2(3methylpyrazinyl)  secbutyl  
A200 (a, b, c, and d)  2(3methylpyrazinyl)  cyclohexyl  
A201 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutoxy  
A202 (a, b, c, and d)  2(3methylpyrazinyl)  isopropoxy  
A203 (a, b, c, and d)  2(3methylpyrazinyl)  —CF_{3}  
A204 (a, b, c, and d)  2(3methylpyrazinyl)  —OCF_{3}  
A205 (a, b, c, and d)  2(3methylpyrazinyl)  —Cl  
A206 (a, b, c, and d)  2(3methylpyrazinyl)  —Br  
A207 (a, b, c, and d)  2(3methylpyrazinyl)  —I  
A208 (a, b, c, and d)  2(3methylpyrazinyl)  nbutyl  
A209 (a, b, c, and d)  2(3methylpyrazinyl)  npropyl  
A210 (a, b, c, and d)  2(3methylpyrazinyl)  isopropyl  
A211 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutyl  
A212 (a, b, c, and d)  2(3fluoropyrazinyl)  isobutyl  
A213 (a, b, c, and d)  2(3fluoropyrazinyl)  secbutyl  
A214 (a, b, c, and d)  2(3fluoropyrazinyl)  cyclohexyl  
A215 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutoxy  
A216 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropoxy  
A217 (a, b, c, and d)  2(3fluoropyrazinyl)  —CF_{3}  
A218 (a, b, c, and d)  2(3fluoropyrazinyl)  —OCF_{3}  
A219 (a, b, c, and d)  2(3fluoropyrazinyl)  —Cl  
A220 (a, b, c, and d)  2(3fluoropyrazinyl)  —Br  
A221 (a, b, c, and d)  2(3fluoropyrazinyl)  —I  
A222 (a, b, c, and d)  2(3fluoropyrazinyl)  nbutyl  
A223 (a, b, c, and d)  2(3fluoropyrazinyl)  npropyl  
A224 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropyl  
A225 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutyl  
A226 (a, b, c, and d)  3(4chloropyridazinyl)  isobutyl  
A227 (a, b, c, and d)  3(4chloropyridazinyl)  secbutyl  
A228 (a, b, c, and d)  3(4chloropyridazinyl)  cyclohexyl  
A229 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutoxy  
A230 (a, b, c, and d)  3(4chloropyridazinyl)  isopropoxy  
A231 (a, b, c, and d)  3(4chloropyridazinyl)  —CF_{3}  
A232 (a, b, c, and d)  3(4chloropyridazinyl)  —OCF_{3}  
A233 (a, b, c, and d)  3(4chloropyridazinyl)  —Cl  
A234 (a, b, c, and d)  3(4chloropyridazinyl)  —Br  
A235 (a, b, c, and d)  3(4chloropyridazinyl)  —I  
A236 (a, b, c, and d)  3(4chloropyridazinyl)  nbutyl  
A237 (a, b, c, and d)  3(4chloropyridazinyl)  npropyl  
A238 (a, b, c, and d)  3(4chloropyridazinyl)  isopropyl  
A239 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutyl  
A240 (a, b, c, and d)  3(4methylpyridazinyl)  isobutyl  
A241 (a, b, c, and d)  3(4methylpyridazinyl)  secbutyl  
A242 (a, b, c, and d)  3(4methylpyridazinyl)  cyclohexyl  
A243 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutoxy  
A244 (a, b, c, and d)  3(4methylpyridazinyl)  isopropoxy  
A245 (a, b, c, and d)  3(4methylpyridazinyl)  —CF_{3}  
A246 (a, b, c, and d)  3(4methylpyridazinyl)  —OCF_{3}  
A247 (a, b, c, and d)  3(4methylpyridazinyl)  —Cl  
A248 (a, b, c, and d)  3(4methylpyridazinyl)  —Br  
A249 (a, b, c, and d)  3(4methylpyridazinyl)  —I  
A250 (a, b, c, and d)  3(4methylpyridazinyl)  nbutyl  
A251 (a, b, c, and d)  3(4methylpyridazinyl)  npropyl  
A252 (a, b, c, and d)  3(4methylpyridazinyl)  isopropyl  
A253 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutyl  
A254 (a, b, c, and d)  3(4fluoropyridazinyl)  isobutyl  
A255 (a, b, c, and d)  3(4fluoropyridazinyl)  secbutyl  
A256 (a, b, c, and d)  3(4fluoropyridazinyl)  cyclohexyl  
A257 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutoxy  
A258 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropoxy  
A259 (a, b, c, and d)  3(4fluoropyridazinyl)  —CF_{3}  
A260 (a, b, c, and d)  3(4fluoropyridazinyl)  —OCF_{3}  
A261 (a, b, c, and d)  3(4fluoropyridazinyl)  —Cl  
A262 (a, b, c, and d)  3(4fluoropyridazinyl)  —Br  
A263 (a, b, c, and d)  3(4fluoropyridazinyl)  —I  
A264 (a, b, c, and d)  3(4fluoropyridazinyl)  nbutyl  
A265 (a, b, c, and d)  3(4fluoropyridazinyl)  npropyl  
A266 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropyl  
A267 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutyl  
A268 (a, b, c, and d)  5(4chlorothiadiazolyl)  isobutyl  
A269 (a, b, c, and d)  5(4chlorothiadiazolyl)  secbutyl  
A270 (a, b, c, and d)  5(4chlorothiadiazolyl)  cyclohexyl  
A271 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutoxy  
A272 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropoxy  
A273 (a, b, c, and d)  5(4chlorothiadiazolyl)  —CF_{3}  
A274 (a, b, c, and d)  5(4chlorothiadiazolyl)  —OCF_{3}  
A275 (a, b, c, and d)  5(4chlorothiadiazolyl)  —Cl  
A276 (a, b, c, and d)  5(4chlorothiadiazolyl)  —Br  
A277 (a, b, c, and d)  5(4chlorothiadiazolyl)  —I  
A278 (a, b, c, and d)  5(4chlorothiadiazolyl)  nbutyl  
A279 (a, b, c, and d)  5(4chlorothiadiazolyl)  npropyl  
A280 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropyl  
A281 (a, b, c, and d)  5(4methylthiadiazolyl)  tertbutyl  
A282 (a, b, c, and d)  5(4methylthiadiazolyl)  isobutyl  
A283 (a, b, c, and d)  5(4methylthiadiazolyl)  secbutyl  
A284 (a, b, c, and d)  5(4methylthiadiazolyl)  cyclohexyl  
A285 (a, b, c, and d)  5(4methylthiadiazolyl)  tertbutoxy  
A286 (a, b, c, and d)  5(4methylthiadiazolyl)  isopropoxy  
A287 (a, b, c, and d)  5(4methylthiadiazolyl)  —CF_{3}  
A288 (a, b, c, and d)  5(4methylthiadiazolyl)  —OCF_{3}  
A289 (a, b, c, and d)  5(4methylthiadiazolyl)  —Cl  
A290 (a, b, c, and d)  5(4methylthiadiazolyl)  —Br  
A291 (a, b, c, and d)  5(4methylthiadiazolyl)  —I  
A292 (a, b, c, and d)  5(4methylthiadiazolyl)  nbutyl  
A293 (a, b, c, and d)  5(4methylthiadiazolyl)  npropyl  
A294 (a, b, c, and d)  5(4methylthiadiazolyl)  isopropyl  
A295 (a, b, c, and d)  5(4fluorothiadiazolyl)  tertbutyl  
A296 (a, b, c, and d)  5(4fluorothiadiazolyl)  isobutyl  
A297 (a, b, c, and d)  5(4fluorothiadiazolyl)  secbutyl  
A298 (a, b, c, and d)  5(4fluorothiadiazolyl)  cyclohexyl  
A299 (a, b, c, and d)  5(4fluorothiadiazolyl)  tertbutoxy  
A300 (a, b, c, and d)  5(4fluorothiadiazolyl)  isopropoxy  
A301 (a, b, c, and d)  5(4fluorothiadiazolyl)  —CF_{3}  
A302 (a, b, c, and d)  5(4fluorothiadiazolyl)  —OCF_{3}  
A303 (a, b, c, and d)  5(4fluorothiadiazolyl)  —Cl  
A304 (a, b, c, and d)  5(4fluorothiadiazolyl)  —Br  
A305 (a, b, c, and d)  5(4fluorothiadiazolyl)  —I  
A306 (a, b, c, and d)  5(4fluorothiadiazolyl)  nbutyl  
A307 (a, b, c, and d)  5(4fluorothiadiazolyl)  npropyl  
A308 (a, b, c, and d)  5(4fluorothiadiazolyl)  isopropyl  
“a” means R_{3 }is —H.  
“b” means R_{3 }is —CH_{3 }and the Nitro(cyano)vinylpiperazine Compound is racemic.  
“c” means R_{3 }is —CH_{3 }and the carbon atom to which R_{3 }is attached is in the (R) configuration.  
“d” means R_{3 }is —CH_{3 }and the carbon atom to which R_{3 }is attached is in the (S) configuration. 
TABLE 2  
(IV)  


and pharmaceutically acceptable salts thereof, where:  
Compound  Ar_{1}  R_{8a}  
B1 (a, b, c, and d)  2(3chloropyridyl)  tertbutyl  
B2 (a, b, c, and d)  2(3chloropyridyl)  isobutyl  
B3 (a, b, c, and d)  2(3chloropyridyl)  secbutyl  
B4 (a, b, c, and d)  2(3chloropyridyl)  cyclohexyl  
B5 (a, b, c, and d)  2(3chloropyridyl)  tertbutoxy  
B6 (a, b, c, and d)  2(3chloropyridyl)  isopropoxy  
B7 (a, b, c, and d)  2(3chloropyridyl)  —CF_{3}  
B8 (a, b, c, and d)  2(3chloropyridyl)  —OCF_{3}  
B9 (a, b, c, and d)  2(3chloropyridyl)  —Cl  
B10 (a, b, c, and d)  2(3chloropyridyl)  —Br  
B11 (a, b, c, and d)  2(3chloropyridyl)  —I  
B12 (a, b, c, and d)  2(3chloropyridyl)  nbutyl  
B13 (a, b, c, and d)  2(3chloropyridyl)  npropyl  
B14 (a, b, c, and d)  2(3chloropyridyl)  isopropyl  
B15 (a, b, c, and d)  2(3fluoropyridyl)  tertbutyl  
B16 (a, b, c, and d)  2(3fluoropyridyl)  isobutyl  
B17 (a, b, c, and d)  2(3fluoropyridyl)  secbutyl  
B18 (a, b, c, and d)  2(3fluoropyridyl)  cyclohexyl  
B19 (a, b, c, and d)  2(3fluoropyridyl)  tertbutoxy  
B20 (a, b, c, and d)  2(3fluoropyridyl)  isopropoxy  
B21 (a, b, c, and d)  2(3fluoropyridyl)  —CF_{3}  
B22 (a, b, c, and d)  2(3fluoropyridyl)  —OCF_{3}  
B23 (a, b, c, and d)  2(3fluoropyridyl)  —Cl  
B24 (a, b, c, and d)  2(3fluoropyridyl)  —Br  
B25 (a, b, c, and d)  2(3fluoropyridyl)  —I  
B26 (a, b, c, and d)  2(3fluoropyridyl)  nbutyl  
B27 (a, b, c, and d)  2(3fluoropyridyl)  npropyl  
B28 (a, b, c, and d)  2(3fluoropyridyl)  isopropyl  
B29 (a, b, c, and d)  2(3methylpyridyl)  tertbutyl  
B30 (a, b, c, and d)  2(3methylpyridyl)  isobutyl  
B31 (a, b, c, and d)  2(3methylpyridyl)  secbutyl  
B32 (a, b, c, and d)  2(3methylpyridyl)  cyclohexyl  
B33 (a, b, c, and d)  2(3methylpyridyl)  tertbutoxy  
B34 (a, b, c, and d)  2(3methylpyridyl)  isopropoxy  
B35 (a, b, c, and d)  2(3methylpyridyl)  —CF_{3}  
B36 (a, b, c, and d)  2(3methylpyridyl)  —OCF_{3}  
B37 (a, b, c, and d)  2(3methylpyridyl)  —Cl  
B38 (a, b, c, and d)  2(3methylpyridyl)  —Br  
B39 (a, b, c, and d)  2(3methylpyridyl)  —I  
B40 (a, b, c, and d)  2(3methylpyridyl)  nbutyl  
B41 (a, b, c, and d)  2(3methylpyridyl)  npropyl  
B42 (a, b, c, and d)  2(3methylpyridyl)  isopropyl  
B43 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutyl  
B44 (a, b, c, and d)  2(3CF_{3}pyridyl)  isobutyl  
B45 (a, b, c, and d)  2(3CF_{3}pyridyl)  secbutyl  
B46 (a, b, c, and d)  2(3CF_{3}pyridyl)  cyclohexyl  
B47 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutoxy  
B48 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropoxy  
B49 (a, b, c, and d)  2(3CF_{3}pyridyl)  —CF_{3}  
B50 (a, b, c, and d)  2(3CF_{3}pyridyl)  —OCF_{3}  
B51 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Cl  
B52 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Br  
B53 (a, b, c, and d)  2(3CF_{3}pyridyl)  —I  
B54 (a, b, c, and d)  2(3CF_{3}pyridyl)  nbutyl  
B55 (a, b, c, and d)  2(3CF_{3}pyridyl)  npropyl  
B56 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropyl  
B57 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutyl  
B58 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isobutyl  
B59 (a, b, c, and d)  2(3CHF_{2}pyridyl)  secbutyl  
B60 (a, b, c, and d)  2(3CHF_{2}pyridyl)  cyclohexyl  
B61 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutoxy  
B62 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropoxy  
B63 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —CF_{3}  
B64 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —OCF_{3}  
B65 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Cl  
B66 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Br  
B67 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —I  
B68 (a, b, c, and d)  2(3CHF_{2}pyridyl)  nbutyl  
B69 (a, b, c, and d)  2(3CHF_{2}pyridyl)  npropyl  
B70 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropyl  
B71 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutyl  
B72 (a, b, c, and d)  2(3hydroxypyridyl)  isobutyl  
B73 (a, b, c, and d)  2(3hydroxypyridyl)  secbutyl  
B74 (a, b, c, and d)  2(3hydroxypyridyl)  cyclohexyl  
B75 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutoxy  
B76 (a, b, c, and d)  2(3hydroxypyridyl)  isopropoxy  
B77 (a, b, c, and d)  2(3hydroxypyridyl)  —CF_{3}  
B78 (a, b, c, and d)  2(3hydroxypyridyl)  —OCF_{3}  
B79 (a, b, c, and d)  2(3hydroxypyridyl)  —Cl  
B80 (a, b, c, and d)  2(3hydroxypyridyl)  —Br  
B81 (a, b, c, and d)  2(3hydroxypyridyl)  —I  
B82 (a, b, c, and d)  2(3hydroxypyridyl)  nbutyl  
B83 (a, b, c, and d)  2(3hydroxypyridyl)  npropyl  
B84 (a, b, c, and d)  2(3hydroxypyridyl)  isopropyl  
B85 (a, b, c, and d)  2(3nitropyridyl)  tertbutyl  
B86 (a, b, c, and d)  2(3nitropyridyl)  isobutyl  
B87 (a, b, c, and d)  2(3nitropyridyl)  secbutyl  
B88 (a, b, c, and d)  2(3nitropyridyl)  cyclohexyl  
B89 (a, b, c, and d)  2(3nitropyridyl)  tertbutoxy  
B90 (a, b, c, and d)  2(3nitropyridyl)  isopropoxy  
B91 (a, b, c, and d)  2(3nitropyridyl)  —CF_{3}  
B92 (a, b, c, and d)  2(3nitropyridyl)  —OCF_{3}  
B93 (a, b, c, and d)  2(3nitropyridyl)  —Cl  
B94 (a, b, c, and d)  2(3nitropyridyl)  —Br  
B95 (a, b, c, and d)  2(3nitropyridyl)  —I  
B96 (a, b, c, and d)  2(3nitropyridyl)  nbutyl  
B97 (a, b, c, and d)  2(3nitropyridyl)  npropyl  
B98 (a, b, c, and d)  2(3nitropyridyl)  isopropyl  
B99 (a, b, c, and d)  2(3cyanopyridyl)  tertbutyl  
B100 (a, b, c, and d)  2(3cyanopyridyl)  isobutyl  
B101 (a, b, c, and d)  2(3cyanopyridyl)  secbutyl  
B102 (a, b, c, and d)  2(3cyanopyridyl)  cyclohexyl  
B103 (a, b, c, and d)  2(3cyanopyridyl)  tertbutoxy  
B104 (a, b, c, and d)  2(3cyanopyridyl)  isopropoxy  
B105 (a, b, c, and d)  2(3cyanopyridyl)  —CF_{3}  
B106 (a, b, c, and d)  2(3cyanopyridyl)  —OCF_{3}  
B107 (a, b, c, and d)  2(3cyanopyridyl)  —Cl  
B108 (a, b, c, and d)  2(3cyanopyridyl)  —Br  
B109 (a, b, c, and d)  2(3cyanopyridyl)  —I  
B110 (a, b, c, and d)  2(3cyanopyridyl)  nbutyl  
B111 (a, b, c, and d)  2(3cyanopyridyl)  npropyl  
B112 (a, b, c, and d)  2(3cyanopyridyl)  isopropyl  
B113 (a, b, c, and d)  2(3bromopyridyl)  tertbutyl  
B114 (a, b, c, and d)  2(3bromopyridyl)  isobutyl  
B115 (a, b, c, and d)  2(3bromopyridyl)  secbutyl  
B116 (a, b, c, and d)  2(3bromopyridyl)  cyclohexyl  
B117 (a, b, c, and d)  2(3bromopyridyl)  tertbutoxy  
B118 (a, b, c, and d)  2(3bromopyridyl)  isopropoxy  
B119 (a, b, c, and d)  2(3bromopyridyl)  —CF_{3}  
B120 (a, b, c, and d)  2(3bromopyridyl)  —OCF_{3}  
B121 (a, b, c, and d)  2(3bromopyridyl)  —Cl  
B122 (a, b, c, and d)  2(3bromopyridyl)  —Br  
B123 (a, b, c, and d)  2(3bromopyridyl)  —I  
B124 (a, b, c, and d)  2(3bromopyridyl)  nbutyl  
B125 (a, b, c, and d)  2(3bromopyridyl)  npropyl  
B126 (a, b, c, and d)  2(3bromopyridyl)  isopropyl  
B127 (a, b, c, and d)  2(3iodopyridyl)  tertbutyl  
B128 (a, b, c, and d)  2(3iodopyridyl)  isobutyl  
B129 (a, b, c, and d)  2(3iodopyridyl)  secbutyl  
B130 (a, b, c, and d)  2(3iodopyridyl)  cyclohexyl  
B131 (a, b, c, and d)  2(3iodopyridyl)  tertbutoxy  
B132 (a, b, c, and d)  2(3iodopyridyl)  isopropoxy  
B133 (a, b, c, and d)  2(3iodopyridyl)  —CF_{3}  
B134 (a, b, c, and d)  2(3iodopyridyl)  —OCF_{3}  
B135 (a, b, c, and d)  2(3iodopyridyl)  —Cl  
B136 (a, b, c, and d)  2(3iodopyridyl)  —Br  
B137 (a, b, c, and d)  2(3iodopyridyl)  —I  
B138 (a, b, c, and d)  2(3iodopyridyl)  nbutyl  
B139 (a, b, c, and d)  2(3iodopyridyl)  npropyl  
B140 (a, b, c, and d)  2(3iodopyridyl)  isopropyl  
B141 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutyl  
B142 (a, b, c, and d)  4(5chloropyrimidinyl)  isobutyl  
B143 (a, b, c, and d)  4(5chloropyrimidinyl)  secbutyl  
B144 (a, b, c, and d)  4(5chloropyrimidinyl)  cyclohexyl  
B145 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutoxy  
B146 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropoxy  
B147 (a, b, c, and d)  4(5chloropyrimidinyl)  —CF_{3}  
B148 (a, b, c, and d)  4(5chloropyrimidinyl)  —OCF_{3}  
B149 (a, b, c, and d)  4(5chloropyrimidinyl)  —Cl  
B150 (a, b, c, and d)  4(5chloropyrimidinyl)  —Br  
B151 (a, b, c, and d)  4(5chloropyrimidinyl)  —I  
B152 (a, b, c, and d)  4(5chloropyrimidinyl)  nbutyl  
B153 (a, b, c, and d)  4(5chloropyrimidinyl)  npropyl  
B154 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropyl  
B155 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutyl  
B156 (a, b, c, and d)  4(5methylpyrimidinyl)  isobutyl  
B157 (a, b, c, and d)  4(5methylpyrimidinyl)  secbutyl  
B158 (a, b, c, and d)  4(5methylpyrimidinyl)  cyclohexyl  
B159 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutoxy  
B160 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropoxy  
B161 (a, b, c, and d)  4(5methylpyrimidinyl)  —CF_{3}  
B162 (a, b, c, and d)  4(5methylpyrimidinyl)  —OCF_{3}  
B163 (a, b, c, and d)  4(5methylpyrimidinyl)  —Cl  
B164 (a, b, c, and d)  4(5methylpyrimidinyl)  —Br  
B165 (a, b, c, and d)  4(5methylpyrimidinyl)  —I  
B166 (a, b, c, and d)  4(5methylpyrimidinyl)  nbutyl  
B167 (a, b, c, and d)  4(5methylpyrimidinyl)  npropyl  
B168 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropyl  
B169 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutyl  
B170 (a, b, c, and d)  4(5fluoropyrimidinyl)  isobutyl  
B171 (a, b, c, and d)  4(5fluoropyrimidinyl)  secbutyl  
B172 (a, b, c, and d)  4(5fluoropyrimidinyl)  cyclohexyl  
B173 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutoxy  
B174 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropoxy  
B175 (a, b, c, and d)  4(5fluoropyrimidinyl)  —CF_{3}  
B176 (a, b, c, and d)  4(5fluoropyrimidinyl)  —OCF_{3}  
B177 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Cl  
B178 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Br  
B179 (a, b, c, and d)  4(5fluoropyrimidinyl)  —I  
B180 (a, b, c, and d)  4(5fluoropyrimidinyl)  nbutyl  
B181 (a, b, c, and d)  4(5fluoropyrimidinyl)  npropyl  
B182 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropyl  
B183 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutyl  
B184 (a, b, c, and d)  2(3chloropyrazinyl)  isobutyl  
B185 (a, b, c, and d)  2(3chloropyrazinyl)  secbutyl  
B186 (a, b, c, and d)  2(3chloropyrazinyl)  cyclohexyl  
B187 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutoxy  
B188 (a, b, c, and d)  2(3chloropyrazinyl)  isopropoxy  
B189 (a, b, c, and d)  2(3chloropyrazinyl)  —CF_{3}  
B190 (a, b, c, and d)  2(3chloropyrazinyl)  —OCF_{3}  
B191 (a, b, c, and d)  2(3chloropyrazinyl)  —Cl  
B192 (a, b, c, and d)  2(3chloropyrazinyl)  —Br  
B193 (a, b, c, and d)  2(3chloropyrazinyl)  —I  
B194 (a, b, c, and d)  2(3chloropyrazinyl)  nbutyl  
B195 (a, b, c, and d)  2(3chloropyrazinyl)  npropyl  
B196 (a, b, c, and d)  2(3chloropyrazinyl)  isopropyl  
B197 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutyl  
B198 (a, b, c, and d)  2(3methylpyrazinyl)  isobutyl  
B199 (a, b, c, and d)  2(3methylpyrazinyl)  secbutyl  
B200 (a, b, c, and d)  2(3methylpyrazinyl)  cyclohexyl  
B201 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutoxy  
B202 (a, b, c, and d)  2(3methylpyrazinyl)  isopropoxy  
B203 (a, b, c, and d)  2(3methylpyrazinyl)  —CF_{3}  
B204 (a, b, c, and d)  2(3methylpyrazinyl)  —OCF_{3}  
B205 (a, b, c, and d)  2(3methylpyrazinyl)  —Cl  
B206 (a, b, c, and d)  2(3methylpyrazinyl)  —Br  
B207 (a, b, c, and d)  2(3methylpyrazinyl)  —I  
B208 (a, b, c, and d)  2(3methylpyrazinyl)  nbutyl  
B209 (a, b, c, and d)  2(3methylpyrazinyl)  npropyl  
B210 (a, b, c, and d)  2(3methylpyrazinyl)  isopropyl  
B211 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutyl  
B212 (a, b, c, and d)  2(3fluoropyrazinyl)  isobutyl  
B213 (a, b, c, and d)  2(3fluoropyrazinyl)  secbutyl  
B214 (a, b, c, and d)  2(3fluoropyrazinyl)  cyclohexyl  
B215 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutoxy  
B216 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropoxy  
B217 (a, b, c, and d)  2(3fluoropyrazinyl)  —CF_{3}  
B218 (a, b, c, and d)  2(3fluoropyrazinyl)  —OCF_{3}  
B219 (a, b, c, and d)  2(3fluoropyrazinyl)  —Cl  
B220 (a, b, c, and d)  2(3fluoropyrazinyl)  —Br  
B221 (a, b, c, and d)  2(3fluoropyrazinyl)  —I  
B222 (a, b, c, and d)  2(3fluoropyrazinyl)  nbutyl  
B223 (a, b, c, and d)  2(3fluoropyrazinyl)  npropyl  
B224 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropyl  
B225 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutyl  
B226 (a, b, c, and d)  3(4chloropyridazinyl)  isobutyl  
B227 (a, b, c, and d)  3(4chloropyridazinyl)  secbutyl  
B228 (a, b, c, and d)  3(4chloropyridazinyl)  cyclohexyl  
B229 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutoxy  
B230 (a, b, c, and d)  3(4chloropyridazinyl)  isopropoxy  
B231 (a, b, c, and d)  3(4chloropyridazinyl)  —CF_{3}  
B232 (a, b, c, and d)  3(4chloropyridazinyl)  —OCF_{3}  
B233 (a, b, c, and d)  3(4chloropyridazinyl)  —Cl  
B234 (a, b, c, and d)  3(4chloropyridazinyl)  —Br  
B235 (a, b, c, and d)  3(4chloropyridazinyl)  —I  
B236 (a, b, c, and d)  3(4chloropyridazinyl)  nbutyl  
B237 (a, b, c, and d)  3(4chloropyridazinyl)  npropyl  
B238 (a, b, c, and d)  3(4chloropyridazinyl)  isopropyl  
B239 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutyl  
B240 (a, b, c, and d)  3(4methylpyridazinyl)  isobutyl  
B241 (a, b, c, and d)  3(4methylpyridazinyl)  secbutyl  
B242 (a, b, c, and d)  3(4methylpyridazinyl)  cyclohexyl  
B243 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutoxy  
B244 (a, b, c, and d)  3(4methylpyridazinyl)  isopropoxy  
B245 (a, b, c, and d)  3(4methylpyridazinyl)  —CF_{3}  
B246 (a, b, c, and d)  3(4methylpyridazinyl)  —OCF_{3}  
B247 (a, b, c, and d)  3(4methylpyridazinyl)  —Cl  
B248 (a, b, c, and d)  3(4methylpyridazinyl)  —Br  
B249 (a, b, c, and d)  3(4methylpyridazinyl)  —I  
B250 (a, b, c, and d)  3(4methylpyridazinyl)  nbutyl  
B251 (a, b, c, and d)  3(4methylpyridazinyl)  npropyl  
B252 (a, b, c, and d)  3(4methylpyridazinyl)  isopropyl  
B253 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutyl  
B254 (a, b, c, and d)  3(4fluoropyridazinyl)  isobutyl  
B255 (a, b, c, and d)  3(4fluoropyridazinyl)  secbutyl  
B256 (a, b, c, and d)  3(4fluoropyridazinyl)  cyclohexyl  
B257 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutoxy  
B258 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropoxy  
B259 (a, b, c, and d)  3(4fluoropyridazinyl)  —CF_{3}  
B260 (a, b, c, and d)  3(4fluoropyridazinyl)  —OCF_{3}  
B261 (a, b, c, and d)  3(4fluoropyridazinyl)  —Cl  
B262 (a, b, c, and d)  3(4fluoropyridazinyl)  —Br  
B263 (a, b, c, and d)  3(4fluoropyridazinyl)  —I  
B264 (a, b, c, and d)  3(4fluoropyridazinyl)  nbutyl  
B265 (a, b, c, and d)  3(4fluoropyridazinyl)  npropyl  
B266 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropyl  
B267 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutyl  
B268 (a, b, c, and d)  5(4chlorothiadiazolyl)  isobutyl  
B269 (a, b, c, and d)  5(4chlorothiadiazolyl)  secbutyl  
B270 (a, b, c, and d)  5(4chlorothiadiazolyl)  cyclohexyl  
B271 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutoxy  
B272 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropoxy  
B273 (a, b, c, and d)  5(4chlorothiadiazolyl)  —CF_{3}  
B274 (a, b, c, and d)  5(4chlorothiadiazolyl)  —OCF_{3}  
B275 (a, b, c, and d)  5(4chlorothiadiazolyl)  —Cl  
B276 (a, b, c, and d)  5(4chlorothiadiazolyl)  —Br  
B277 (a, b, c, and d)  5(4chlorothiadiazolyl)  —I  
B278 (a, b, c, and d)  5(4chlorothiadiazolyl)  nbutyl  
B279 (a, b, c, and d)  5(4chlorothiadiazolyl)  npropyl  
B280 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropyl  
B281 (a, b, c, and d)  5(4methylthiadiazolyl)  tertbutyl  
B282 (a, b, c, and d)  5(4methylthiadiazolyl)  isobutyl  
B283 (a, b, c, and d)  5(4methylthiadiazolyl)  secbutyl  
B284 (a, b, c, and d)  5(4methylthiadiazolyl)  cyclohexyl  
B285 (a, b, c, and d)  5(4methylthiadiazolyl)  tertbutoxy  
B286 (a, b, c, and d)  5(4methylthiadiazolyl)  isopropoxy  
B287 (a, b, c, and d)  5(4methylthiadiazolyl)  —CF_{3}  
B288 (a, b, c, and d)  5(4methylthiadiazolyl)  —OCF_{3}  
B289 (a, b, c, and d)  5(4methylthiadiazolyl)  —Cl  
B290 (a, b, c, and d)  5(4methylthiadiazolyl)  —Br  
B291 (a, b, c, and d)  5(4methylthiadiazolyl)  —I  
B292 (a, b, c, and d)  5(4methylthiadiazolyl)  nbutyl  
B293 (a, b, c, and d)  5(4methylthiadiazolyl)  npropyl  
B294 (a, b, c, and d)  5(4methylthiadiazolyl)  isopropyl  
B295 (a, b, c, and d)  5(4fluorothiadiazolyl)  tertbutyl  
B296 (a, b, c, and d)  5(4fluorothiadiazolyl)  isobutyl  
B297 (a, b, c, and d)  5(4fluorothiadiazolyl)  secbutyl  
B298 (a, b, c, and d)  5(4fluorothiadiazolyl)  cyclohexyl  
B299 (a, b, c, and d)  5(4fluorothiadiazolyl)  tertbutoxy  
B300 (a, b, c, and d)  5(4fluorothiadiazolyl)  isopropoxy  
B301 (a, b, c, and d)  5(4fluorothiadiazolyl)  —CF_{3}  
B302 (a, b, c, and d)  5(4fluorothiadiazolyl)  —OCF_{3}  
B303 (a, b, c, and d)  5(4fluorothiadiazolyl)  —Cl  
B304 (a, b, c, and d)  5(4fluorothiadiazolyl)  —Br  
B305 (a, b, c, and d)  5(4fluorothiadiazolyl)  —I  
B306 (a, b, c, and d)  5(4fluorothiadiazolyl)  nbutyl  
B307 (a, b, c, and d)  5(4fluorothiadiazolyl)  npropyl  
B308 (a, b, c, and d)  5(4fluorothiadiazolyl)  isopropyl  
“a” means R_{3 }is —H.  
“b” means R_{3 }is —CH_{3 }and the Nitro(cyano)vinylpiperazine Compound is racemic.  
“c” means R_{3 }is —CH_{3 }and the carbon atom to which R_{3 }is attached is in the (R) configuration.  
“d” means R_{3 }is —CH_{3 }and the carbon atom to which R_{3 }is attached is in the (S) configuration. 
TABLE 3  
(V)  


and pharmaceutically acceptable salts thereof, where:  
Compound  Ar_{1}  R_{8a}  
C1 (a, b, c, and d)  2(3chloropyridyl)  tertbutyl  
C2 (a, b, c, and d)  2(3chloropyridyl)  isobutyl  
C3 (a, b, c, and d)  2(3chloropyridyl)  secbutyl  
C4 (a, b, c, and d)  2(3chloropyridyl)  cyclohexyl  
C5 (a, b, c, and d)  2(3chloropyridyl)  tertbutoxy  
C6 (a, b, c, and d)  2(3chloropyridyl)  isopropoxy  
C7 (a, b, c, and d)  2(3chloropyridyl)  —CF_{3}  
C8 (a, b, c, and d)  2(3chloropyridyl)  —OCF_{3}  
C9 (a, b, c, and d)  2(3chloropyridyl)  —Cl  
C10 (a, b, c, and d)  2(3chloropyridyl)  —Br  
C11 (a, b, c, and d)  2(3chloropyridyl)  —I  
C12 (a, b, c, and d)  2(3chloropyridyl)  nbutyl  
C13 (a, b, c, and d)  2(3chloropyridyl)  npropyl  
C14 (a, b, c, and d)  2(3chloropyridyl)  isopropyl  
C15 (a, b, c, and d)  2(3fluoropyridyl)  tertbutyl  
C16 (a, b, c, and d)  2(3fluoropyridyl)  isobutyl  
C17 (a, b, c, and d)  2(3fluoropyridyl)  secbutyl  
C18 (a, b, c, and d)  2(3fluoropyridyl)  cyclohexyl  
C19 (a, b, c, and d)  2(3fluoropyridyl)  tertbutoxy  
C20 (a, b, c, and d)  2(3fluoropyridyl)  isopropoxy  
C21 (a, b, c, and d)  2(3fluoropyridyl)  —CF_{3}  
C22 (a, b, c, and d)  2(3fluoropyridyl)  —OCF_{3}  
C23 (a, b, c, and d)  2(3fluoropyridyl)  —Cl  
C24 (a, b, c, and d)  2(3fluoropyridyl)  —Br  
C25 (a, b, c, and d)  2(3fluoropyridyl)  —I  
C26 (a, b, c, and d)  2(3fluoropyridyl)  nbutyl  
C27 (a, b, c, and d)  2(3fluoropyridyl)  npropyl  
C28 (a, b, c, and d)  2(3fluoropyridyl)  isopropyl  
C29 (a, b, c, and d)  2(3methylpyridyl)  tertbutyl  
C30 (a, b, c, and d)  2(3methylpyridyl)  isobutyl  
C31 (a, b, c, and d)  2(3methylpyridyl)  secbutyl  
C32 (a, b, c, and d)  2(3methylpyridyl)  cyclohexyl  
C33 (a, b, c, and d)  2(3methylpyridyl)  tertbutoxy  
C34 (a, b, c, and d)  2(3methylpyridyl)  isopropoxy  
C35 (a, b, c, and d)  2(3methylpyridyl)  —CF_{3}  
C36 (a, b, c, and d)  2(3methylpyridyl)  —OCF_{3}  
C37 (a, b, c, and d)  2(3methylpyridyl)  —Cl  
C38 (a, b, c, and d)  2(3methylpyridyl)  —Br  
C39 (a, b, c, and d)  2(3methylpyridyl)  —I  
C40 (a, b, c, and d)  2(3methylpyridyl)  nbutyl  
C41 (a, b, c, and d)  2(3methylpyridyl)  npropyl  
C42 (a, b, c, and d)  2(3methylpyridyl)  isopropyl  
C43 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutyl  
C44 (a, b, c, and d)  2(3CF_{3}pyridyl)  isobutyl  
C45 (a, b, c, and d)  2(3CF_{3}pyridyl)  secbutyl  
C46 (a, b, c, and d)  2(3CF_{3}pyridyl)  cyclohexyl  
C47 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutoxy  
C48 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropoxy  
C49 (a, b, c, and d)  2(3CF_{3}pyridyl)  —CF_{3}  
C50 (a, b, c, and d)  2(3CF_{3}pyridyl)  —OCF_{3}  
C51 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Cl  
C52 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Br  
C53 (a, b, c, and d)  2(3CF_{3}pyridyl)  —I  
C54 (a, b, c, and d)  2(3CF_{3}pyridyl)  nbutyl  
C55 (a, b, c, and d)  2(3CF_{3}pyridyl)  npropyl  
C56 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropyl  
C57 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutyl  
C58 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isobutyl  
C59 (a, b, c, and d)  2(3CHF_{2}pyridyl)  secbutyl  
C60 (a, b, c, and d)  2(3CHF_{2}pyridyl)  cyclohexyl  
C61 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutoxy  
C62 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropoxy  
C63 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —CF_{3}  
C64 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —OCF_{3}  
C65 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Cl  
C66 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Br  
C67 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —I  
C68 (a, b, c, and d)  2(3CHF_{2}pyridyl)  nbutyl  
C69 (a, b, c, and d)  2(3CHF_{2}pyridyl)  npropyl  
C70 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropyl  
C71 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutyl  
C72 (a, b, c, and d)  2(3hydroxypyridyl)  isobutyl  
C73 (a, b, c, and d)  2(3hydroxypyridyl)  secbutyl  
C74 (a, b, c, and d)  2(3hydroxypyridyl)  cyclohexyl  
C75 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutoxy  
C76 (a, b, c, and d)  2(3hydroxypyridyl)  isopropoxy  
C77 (a, b, c, and d)  2(3hydroxypyridyl)  —CF_{3}  
C78 (a, b, c, and d)  2(3hydroxypyridyl)  —OCF_{3}  
C79 (a, b, c, and d)  2(3hydroxypyridyl)  —Cl  
C80 (a, b, c, and d)  2(3hydroxypyridyl)  —Br  
C81 (a, b, c, and d)  2(3hydroxypyridyl)  —I  
C82 (a, b, c, and d)  2(3hydroxypyridyl)  nbutyl  
C83 (a, b, c, and d)  2(3hydroxypyridyl)  npropyl  
C84 (a, b, c, and d)  2(3hydroxypyridyl)  isopropyl  
C85 (a, b, c, and d)  2(3nitropyridyl)  tertbutyl  
C86 (a, b, c, and d)  2(3nitropyridyl)  isobutyl  
C87 (a, b, c, and d)  2(3nitropyridyl)  secbutyl  
C88 (a, b, c, and d)  2(3nitropyridyl)  cyclohexyl  
C89 (a, b, c, and d)  2(3nitropyridyl)  tertbutoxy  
C90 (a, b, c, and d)  2(3nitropyridyl)  isopropoxy  
C91 (a, b, c, and d)  2(3nitropyridyl)  —CF_{3}  
C92 (a, b, c, and d)  2(3nitropyridyl)  —OCF_{3}  
C93 (a, b, c, and d)  2(3nitropyridyl)  —Cl  
C94 (a, b, c, and d)  2(3nitropyridyl)  —Br  
C95 (a, b, c, and d)  2(3nitropyridyl)  —I  
C96 (a, b, c, and d)  2(3nitropyridyl)  nbutyl  
C97 (a, b, c, and d)  2(3nitropyridyl)  npropyl  
C98 (a, b, c, and d)  2(3nitropyridyl)  isopropyl  
C99 (a, b, c, and d)  2(3cyanopyridyl)  tertbutyl  
C100 (a, b, c, and d)  2(3cyanopyridyl)  isobutyl  
C101 (a, b, c, and d)  2(3cyanopyridyl)  secbutyl  
C102 (a, b, c, and d)  2(3cyanopyridyl)  cyclohexyl  
C103 (a, b, c, and d)  2(3cyanopyridyl)  tertbutoxy  
C104 (a, b, c, and d)  2(3cyanopyridyl)  isopropoxy  
C105 (a, b, c, and d)  2(3cyanopyridyl)  —CF_{3}  
C106 (a, b, c, and d)  2(3cyanopyridyl)  —OCF_{3}  
C107 (a, b, c, and d)  2(3cyanopyridyl)  —Cl  
C108 (a, b, c, and d)  2(3cyanopyridyl)  —Br  
C109 (a, b, c, and d)  2(3cyanopyridyl)  —I  
C110 (a, b, c, and d)  2(3cyanopyridyl)  nbutyl  
C111 (a, b, c, and d)  2(3cyanopyridyl)  npropyl  
C112 (a, b, c, and d)  2(3cyanopyridyl)  isopropyl  
C113 (a, b, c, and d)  2(3bromopyridyl)  tertbutyl  
C114 (a, b, c, and d)  2(3bromopyridyl)  isobutyl  
C115 (a, b, c, and d)  2(3bromopyridyl)  secbutyl  
C116 (a, b, c, and d)  2(3bromopyridyl)  cyclohexyl  
C117 (a, b, c, and d)  2(3bromopyridyl)  tertbutoxy  
C118 (a, b, c, and d)  2(3bromopyridyl)  isopropoxy  
C119 (a, b, c, and d)  2(3bromopyridyl)  —CF_{3}  
C120 (a, b, c, and d)  2(3bromopyridyl)  —OCF_{3}  
C121 (a, b, c, and d)  2(3bromopyridyl)  —Cl  
C122 (a, b, c, and d)  2(3bromopyridyl)  —Br  
C123 (a, b, c, and d)  2(3bromopyridyl)  —I  
C124 (a, b, c, and d)  2(3bromopyridyl)  nbutyl  
C125 (a, b, c, and d)  2(3bromopyridyl)  npropyl  
C126 (a, b, c, and d)  2(3bromopyridyl)  isopropyl  
C127 (a, b, c, and d)  2(3iodopyridyl)  tertbutyl  
C128 (a, b, c, and d)  2(3iodopyridyl)  isobutyl  
C129 (a, b, c, and d)  2(3iodopyridyl)  secbutyl  
C130 (a, b, c, and d)  2(3iodopyridyl)  cyclohexyl  
C131 (a, b, c, and d)  2(3iodopyridyl)  tertbutoxy  
C132 (a, b, c, and d)  2(3iodopyridyl)  isopropoxy  
C133 (a, b, c, and d)  2(3iodopyridyl)  —CF_{3}  
C134 (a, b, c, and d)  2(3iodopyridyl)  —OCF_{3}  
C135 (a, b, c, and d)  2(3iodopyridyl)  —Cl  
C136 (a, b, c, and d)  2(3iodopyridyl)  —Br  
C137 (a, b, c, and d)  2(3iodopyridyl)  —I  
C138 (a, b, c, and d)  2(3iodopyridyl)  nbutyl  
C139 (a, b, c, and d)  2(3iodopyridyl)  npropyl  
C140 (a, b, c, and d)  2(3iodopyridyl)  isopropyl  
C141 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutyl  
C142 (a, b, c, and d)  4(5chloropyrimidinyl)  isobutyl  
C143 (a, b, c, and d)  4(5chloropyrimidinyl)  secbutyl  
C144 (a, b, c, and d)  4(5chloropyrimidinyl)  cyclohexyl  
C145 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutoxy  
C146 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropoxy  
C147 (a, b, c, and d)  4(5chloropyrimidinyl)  —CF_{3}  
C148 (a, b, c, and d)  4(5chloropyrimidinyl)  —OCF_{3}  
C149 (a, b, c, and d)  4(5chloropyrimidinyl)  —Cl  
C150 (a, b, c, and d)  4(5chloropyrimidinyl)  —Br  
C151 (a, b, c, and d)  4(5chloropyrimidinyl)  —I  
C152 (a, b, c, and d)  4(5chloropyrimidinyl)  nbutyl  
C153 (a, b, c, and d)  4(5chloropyrimidinyl)  npropyl  
C154 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropyl  
C155 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutyl  
C156 (a, b, c, and d)  4(5methylpyrimidinyl)  isobutyl  
C157 (a, b, c, and d)  4(5methylpyrimidinyl)  secbutyl  
C158 (a, b, c, and d)  4(5methylpyrimidinyl)  cyclohexyl  
C159 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutoxy  
C160 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropoxy  
C161 (a, b, c, and d)  4(5methylpyrimidinyl)  —CF_{3}  
C162 (a, b, c, and d)  4(5methylpyrimidinyl)  —OCF_{3}  
C163 (a, b, c, and d)  4(5methylpyrimidinyl)  —Cl  
C164 (a, b, c, and d)  4(5methylpyrimidinyl)  —Br  
C165 (a, b, c, and d)  4(5methylpyrimidinyl)  —I  
C166 (a, b, c, and d)  4(5methylpyrimidinyl)  nbutyl  
C167 (a, b, c, and d)  4(5methylpyrimidinyl)  npropyl  
C168 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropyl  
C169 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutyl  
C170 (a, b, c, and d)  4(5fluoropyrimidinyl)  isobutyl  
C171 (a, b, c, and d)  4(5fluoropyrimidinyl)  secbutyl  
C172 (a, b, c, and d)  4(5fluoropyrimidinyl)  cyclohexyl  
C173 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutoxy  
C174 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropoxy  
C175 (a, b, c, and d)  4(5fluoropyrimidinyl)  —CF_{3}  
C176 (a, b, c, and d)  4(5fluoropyrimidinyl)  —OCF_{3}  
C177 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Cl  
C178 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Br  
C179 (a, b, c, and d)  4(5fluoropyrimidinyl)  —I  
C180 (a, b, c, and d)  4(5fluoropyrimidinyl)  nbutyl  
C181 (a, b, c, and d)  4(5fluoropyrimidinyl)  npropyl  
C182 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropyl  
C183 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutyl  
C184 (a, b, c, and d)  2(3chloropyrazinyl)  isobutyl  
C185 (a, b, c, and d)  2(3chloropyrazinyl)  secbutyl  
C186 (a, b, c, and d)  2(3chloropyrazinyl)  cyclohexyl  
C187 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutoxy  
C188 (a, b, c, and d)  2(3chloropyrazinyl)  isopropoxy  
C189 (a, b, c, and d)  2(3chloropyrazinyl)  —CF_{3}  
C190 (a, b, c, and d)  2(3chloropyrazinyl)  —OCF_{3}  
C191 (a, b, c, and d)  2(3chloropyrazinyl)  —Cl  
C192 (a, b, c, and d)  2(3chloropyrazinyl)  —Br  
C193 (a, b, c, and d)  2(3chloropyrazinyl)  —I  
C194 (a, b, c, and d)  2(3chloropyrazinyl)  nbutyl  
C195 (a, b, c, and d)  2(3chloropyrazinyl)  npropyl  
C196 (a, b, c, and d)  2(3chloropyrazinyl)  isopropyl  
C197 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutyl  
C198 (a, b, c, and d)  2(3methylpyrazinyl)  isobutyl  
C199 (a, b, c, and d)  2(3methylpyrazinyl)  secbutyl  
C200 (a, b, c, and d)  2(3methylpyrazinyl)  cyclohexyl  
C201 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutoxy  
C202 (a, b, c, and d)  2(3methylpyrazinyl)  isopropoxy  
C203 (a, b, c, and d)  2(3methylpyrazinyl)  —CF_{3}  
C204 (a, b, c, and d)  2(3methylpyrazinyl)  —OCF_{3}  
C205 (a, b, c, and d)  2(3methylpyrazinyl)  —Cl  
C206 (a, b, c, and d)  2(3methylpyrazinyl)  —Br  
C207 (a, b, c, and d)  2(3methylpyrazinyl)  —I  
C208 (a, b, c, and d)  2(3methylpyrazinyl)  nbutyl  
C209 (a, b, c, and d)  2(3methylpyrazinyl)  npropyl  
C210 (a, b, c, and d)  2(3methylpyrazinyl)  isopropyl  
C211 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutyl  
C212 (a, b, c, and d)  2(3fluoropyrazinyl)  isobutyl  
C213 (a, b, c, and d)  2(3fluoropyrazinyl)  secbutyl  
C214 (a, b, c, and d)  2(3fluoropyrazinyl)  cyclohexyl  
C215 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutoxy  
C216 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropoxy  
C217 (a, b, c, and d)  2(3fluoropyrazinyl)  —CF_{3}  
C218 (a, b, c, and d)  2(3fluoropyrazinyl)  —OCF_{3}  
C219 (a, b, c, and d)  2(3fluoropyrazinyl)  —Cl  
C220 (a, b, c, and d)  2(3fluoropyrazinyl)  —Br  
C221 (a, b, c, and d)  2(3fluoropyrazinyl)  —I  
C222 (a, b, c, and d)  2(3fluoropyrazinyl)  nbutyl  
C223 (a, b, c, and d)  2(3fluoropyrazinyl)  npropyl  
C224 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropyl  
C225 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutyl  
C226 (a, b, c, and d)  3(4chloropyridazinyl)  isobutyl  
C227 (a, b, c, and d)  3(4chloropyridazinyl)  secbutyl  
C228 (a, b, c, and d)  3(4chloropyridazinyl)  cyclohexyl  
C229 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutoxy  
C230 (a, b, c, and d)  3(4chloropyridazinyl)  isopropoxy  
C231 (a, b, c, and d)  3(4chloropyridazinyl)  —CF_{3}  
C232 (a, b, c, and d)  3(4chloropyridazinyl)  —OCF_{3}  
C233 (a, b, c, and d)  3(4chloropyridazinyl)  —Cl  
C234 (a, b, c, and d)  3(4chloropyridazinyl)  —Br  
C235 (a, b, c, and d)  3(4chloropyridazinyl)  —I  
C236 (a, b, c, and d)  3(4chloropyridazinyl)  nbutyl  
C237 (a, b, c, and d)  3(4chloropyridazinyl)  npropyl  
C238 (a, b, c, and d)  3(4chloropyridazinyl)  isopropyl  
C239 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutyl  
C240 (a, b, c, and d)  3(4methylpyridazinyl)  isobutyl  
C241 (a, b, c, and d)  3(4methylpyridazinyl)  secbutyl  
C242 (a, b, c, and d)  3(4methylpyridazinyl)  cyclohexyl  
C243 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutoxy  
C244 (a, b, c, and d)  3(4methylpyridazinyl)  isopropoxy  
C245 (a, b, c, and d)  3(4methylpyridazinyl)  —CF_{3}  
C246 (a, b, c, and d)  3(4methylpyridazinyl)  —OCF_{3}  
C247 (a, b, c, and d)  3(4methylpyridazinyl)  —Cl  
C248 (a, b, c, and d)  3(4methylpyridazinyl)  —Br  
C249 (a, b, c, and d)  3(4methylpyridazinyl)  —I  
C250 (a, b, c, and d)  3(4methylpyridazinyl)  nbutyl  
C251 (a, b, c, and d)  3(4methylpyridazinyl)  npropyl  
C252 (a, b, c, and d)  3(4methylpyridazinyl)  isopropyl  
C253 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutyl  
C254 (a, b, c, and d)  3(4fluoropyridazinyl)  isobutyl  
C255 (a, b, c, and d)  3(4fluoropyridazinyl)  secbutyl  
C256 (a, b, c, and d)  3(4fluoropyridazinyl)  cyclohexyl  
C257 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutoxy  
C258 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropoxy  
C259 (a, b, c, and d)  3(4fluoropyridazinyl)  —CF_{3}  
C260 (a, b, c, and d)  3(4fluoropyridazinyl)  —OCF_{3}  
C261 (a, b, c, and d)  3(4fluoropyridazinyl)  —Cl  
C262 (a, b, c, and d)  3(4fluoropyridazinyl)  —Br  
C263 (a, b, c, and d)  3(4fluoropyridazinyl)  —I  
C264 (a, b, c, and d)  3(4fluoropyridazinyl)  nbutyl  
C265 (a, b, c, and d)  3(4fluoropyridazinyl)  npropyl  
C266 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropyl  
C267 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutyl  
C268 (a, b, c, and d)  5(4chlorothiadiazolyl)  isobutyl  
C269 (a, b, c, and d)  5(4chlorothiadiazolyl)  secbutyl  
C270 (a, b, c, and d)  5(4chlorothiadiazolyl)  cyclohexyl  
C271 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutoxy  
C272 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropoxy  
C273 (a, b, c, and d)  5(4chlorothiadiazolyl)  —CF_{3}  
C274 (a, b, c, and d)  5(4chlorothiadiazolyl)  —OCF_{3}  
C275 (a, b, c, and d)  5(4chlorothiadiazolyl)  —Cl  
C276 (a, b, c, and d)  5(4chlorothiadiazolyl)  —Br  
C277 (a, b, c, and d)  5(4chlorothiadiazolyl)  —I  
C278 (a, b, c, and d)  5(4chlorothiadiazolyl)  nbutyl  
C279 (a, b, c, and d)  5(4chlorothiadiazolyl)  npropyl  
C280 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropyl  
C281 (a, b, c, and d)  5(4methylthiadiazolyl)  tertbutyl  
C282 (a, b, c, and d)  5(4methylthiadiazolyl)  isobutyl  
C283 (a, b, c, and d)  5(4methylthiadiazolyl)  secbutyl  
C284 (a, b, c, and d)  5(4methylthiadiazolyl)  cyclohexyl  
C285 (a, b, c, and d)  5(4methylthiadiazolyl)  tertbutoxy  
C286 (a, b, c, and d)  5(4methylthiadiazolyl)  isopropoxy  
C287 (a, b, c, and d)  5(4methylthiadiazolyl)  —CF_{3}  
C288 (a, b, c, and d)  5(4methylthiadiazolyl)  —OCF_{3}  
C289 (a, b, c, and d)  5(4methylthiadiazolyl)  —Cl  
C290 (a, b, c, and d)  5(4methylthiadiazolyl)  —Br  
C291 (a, b, c, and d)  5(4methylthiadiazolyl)  —I  
C292 (a, b, c, and d)  5(4methylthiadiazolyl)  nbutyl  
C293 (a, b, c, and d)  5(4methylthiadiazolyl)  npropyl  
C294 (a, b, c, and d)  5(4methylthiadiazolyl)  isopropyl  
C295 (a, b, c, and d)  5(4fluorothiadiazolyl)  tertbutyl  
C296 (a, b, c, and d)  5(4fluorothiadiazolyl)  isobutyl  
C297 (a, b, c, and d)  5(4fluorothiadiazolyl)  secbutyl  
C298 (a, b, c, and d)  5(4fluorothiadiazolyl)  cyclohexyl  
C299 (a, b, c, and d)  5(4fluorothiadiazolyl)  tertbutoxy  
C300 (a, b, c, and d)  5(4fluorothiadiazolyl)  isopropoxy  
C301 (a, b, c, and d)  5(4fluorothiadiazolyl)  —CF_{3}  
C302 (a, b, c, and d)  5(4fluorothiadiazolyl)  —OCF_{3}  
C303 (a, b, c, and d)  5(4fluorothiadiazolyl)  —Cl  
C304 (a, b, c, and d)  5(4fluorothiadiazolyl)  —Br  
C305 (a, b, c, and d)  5(4fluorothiadiazolyl)  —I  
C306 (a, b, c, and d)  5(4fluorothiadiazolyl)  nbutyl  
C307 (a, b, c, and d)  5(4fluorothiadiazolyl)  npropyl  
C308 (a, b, c, and d)  5(4fluorothiadiazolyl)  isopropyl  
“a” means R_{3 }is —H.  
“b” means R_{3 }is —CH_{3 }and the Nitro(cyano)vinylpiperazine Compound is racemic.  
“c” means R_{3 }is —CH_{3 }and the carbon atom to which R_{3 }is attached is in the (R) configuration.  
“d” means R_{3 }is —CH_{3 }and the carbon atom to which R_{3 }is attached is in the (S) configuration. 
TABLE 4  
(VI)  


and pharmaceutically acceptable salts thereof, where:  
Compound  Ar_{1}  R_{8a}  
D1 (a, b, c, and d)  2(3chloropyridyl)  tertbutyl  
D2 (a, b, c, and d)  2(3chloropyridyl)  isobutyl  
D3 (a, b, c, and d)  2(3chloropyridyl)  secbutyl  
D4 (a, b, c, and d)  2(3chloropyridyl)  cyclohexyl  
D5 (a, b, c, and d)  2(3chloropyridyl)  tertbutoxy  
D6 (a, b, c, and d)  2(3chloropyridyl)  isopropoxy  
D7 (a, b, c, and d)  2(3chloropyridyl)  —CF_{3}  
D8 (a, b, c, and d)  2(3chloropyridyl)  —OCF_{3}  
D9 (a, b, c, and d)  2(3chloropyridyl)  —Cl  
D10 (a, b, c, and d)  2(3chloropyridyl)  —Br  
D11 (a, b, c, and d)  2(3chloropyridyl)  —I  
D12 (a, b, c, and d)  2(3chloropyridyl)  nbutyl  
D13 (a, b, c, and d)  2(3chloropyridyl)  npropyl  
D14 (a, b, c, and d)  2(3chloropyridyl)  isopropyl  
D15 (a, b, c, and d)  2(3fluoropyridyl)  tertbutyl  
D16 (a, b, c, and d)  2(3fluoropyridyl)  isobutyl  
D17 (a, b, c, and d)  2(3fluoropyridyl)  secbutyl  
D18 (a, b, c, and d)  2(3fluoropyridyl)  cyclohexyl  
D19 (a, b, c, and d)  2(3fluoropyridyl)  tertbutoxy  
D20 (a, b, c, and d)  2(3fluoropyridyl)  isopropoxy  
D21 (a, b, c, and d)  2(3fluoropyridyl)  —CF_{3}  
D22 (a, b, c, and d)  2(3fluoropyridyl)  —OCF_{3}  
D23 (a, b, c, and d)  2(3fluoropyridyl)  —Cl  
D24 (a, b, c, and d)  2(3fluoropyridyl)  —Br  
D25 (a, b, c, and d)  2(3fluoropyridyl)  —I  
D26 (a, b, c, and d)  2(3fluoropyridyl)  nbutyl  
D27 (a, b, c, and d)  2(3fluoropyridyl)  npropyl  
D28 (a, b, c, and d)  2(3fluoropyridyl)  isopropyl  
D29 (a, b, c, and d)  2(3methylpyridyl)  tertbutyl  
D30 (a, b, c, and d)  2(3methylpyridyl)  isobutyl  
D31 (a, b, c, and d)  2(3methylpyridyl)  secbutyl  
D32 (a, b, c, and d)  2(3methylpyridyl)  cyclohexyl  
D33 (a, b, c, and d)  2(3methylpyridyl)  tertbutoxy  
D34 (a, b, c, and d)  2(3methylpyridyl)  isopropoxy  
D35 (a, b, c, and d)  2(3methylpyridyl)  —CF_{3}  
D36 (a, b, c, and d)  2(3methylpyridyl)  —OCF_{3}  
D37 (a, b, c, and d)  2(3methylpyridyl)  —Cl  
D38 (a, b, c, and d)  2(3methylpyridyl)  —Br  
D39 (a, b, c, and d)  2(3methylpyridyl)  —I  
D40 (a, b, c, and d)  2(3methylpyridyl)  nbutyl  
D41 (a, b, c, and d)  2(3methylpyridyl)  npropyl  
D42 (a, b, c, and d)  2(3methylpyndyl)  isopropyl  
D43 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutyl  
D44 (a, b, c, and d)  2(3CF_{3}pyridyl)  isobutyl  
D45 (a, b, c, and d)  2(3CF_{3}pyridyl)  secbutyl  
D46 (a, b, c, and d)  2(3CF_{3}pyridyl)  cyclohexyl  
D47 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutoxy  
D48 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropoxy  
D49 (a, b, c, and d)  2(3CF_{3}pyridyl)  —CF_{3}  
D50 (a, b, c, and d)  2(3CF_{3}pyridyl)  —OCF_{3}  
D51 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Cl  
D52 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Br  
D53 (a, b, c, and d)  2(3CF_{3}pyridyl)  —I  
D54 (a, b, c, and d)  2(3CF_{3}pyridyl)  nbutyl  
D55 (a, b, c, and d)  2(3CF_{3}pyridyl)  npropyl  
D56 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropyl  
D57 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutyl  
D58 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isobutyl  
D59 (a, b, c, and d)  2(3CHF_{2}pyridyl)  secbutyl  
D60 (a, b, c, and d)  2(3CHF_{2}pyridyl)  cyclohexyl  
D61 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutoxy  
D62 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropoxy  
D63 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —CF_{3}  
D64 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —OCF_{3}  
D65 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Cl  
D66 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Br  
D67 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —I  
D68 (a, b, c, and d)  2(3CHF_{2}pyridyl)  nbutyl  
D69 (a, b, c, and d)  2(3CHF_{2}pyridyl)  npropyl  
D70 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropyl  
D71 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutyl  
D72 (a, b, c, and d)  2(3hydroxypyridyl)  isobutyl  
D73 (a, b, c, and d)  2(3hydroxypyridyl)  secbutyl  
D74 (a, b, c, and d)  2(3hydroxypyridyl)  cyclohexyl  
D75 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutoxy  
D76 (a, b, c, and d)  2(3hydroxypyridyl)  isopropoxy  
D77 (a, b, c, and d)  2(3hydroxypyridyl)  —CF_{3}  
D78 (a, b, c, and d)  2(3hydroxypyridyl)  —OCF_{3}  
D79 (a, b, c, and d)  2(3hydroxypyridyl)  —Cl  
D80 (a, b, c, and d)  2(3hydroxypyridyl)  —Br  
D81 (a, b, c, and d)  2(3hydroxypyridyl)  —I  
D82 (a, b, c, and d)  2(3hydroxypyridyl)  nbutyl  
D83 (a, b, c, and d)  2(3hydroxypyridyl)  npropyl  
D84 (a, b, c, and d)  2(3hydroxypyridyl)  isopropyl  
D85 (a, b, c, and d)  2(3nitropyridyl)  tertbutyl  
D86 (a, b, c, and d)  2(3nitropyridyl)  isobutyl  
D87 (a, b, c, and d)  2(3nitropyridyl)  secbutyl  
D88 (a, b, c, and d)  2(3nitropyridyl)  cyclohexyl  
D89 (a, b, c, and d)  2(3nitropyridyl)  tertbutoxy  
D90 (a, b, c, and d)  2(3nitropyridyl)  isopropoxy  
D91 (a, b, c, and d)  2(3nitropyridyl)  —CF_{3}  
D92 (a, b, c, and d)  2(3nitropyridyl)  —OCF_{3}  
D93 (a, b, c, and d)  2(3nitropyridyl)  —Cl  
D94 (a, b, c, and d)  2(3nitropyridyl)  —Br  
D95 (a, b, c, and d)  2(3nitropyridyl)  —I  
D96 (a, b, c, and d)  2(3nitropyridyl)  nbutyl  
D97 (a, b, c, and d)  2(3nitropyridyl)  npropyl  
D98 (a, b, c, and d)  2(3nitropyridyl)  isopropyl  
D99 (a, b, c, and d)  2(3cyanopyridyl)  tertbutyl  
D100 (a, b, c, and d)  2(3cyanopyridyl)  isobutyl  
D101 (a, b, c, and d)  2(3cyanopyridyl)  secbutyl  
D102 (a, b, c, and d)  2(3cyanopyridyl)  cyclohexyl  
D103 (a, b, c, and d)  2(3cyanopyridyl)  tertbutoxy  
D104 (a, b, c, and d)  2(3cyanopyridyl)  isopropoxy  
D105 (a, b, c, and d)  2(3cyanopyridyl)  —CF_{3}  
D106 (a, b, c, and d)  2(3cyanopyridyl)  —OCF_{3}  
D107 (a, b, c, and d)  2(3cyanopyridyl)  —Cl  
D108 (a, b, c, and d)  2(3cyanopyridyl)  —Br  
D109 (a, b, c, and d)  2(3cyanopyridyl)  —I  
D110 (a, b, c, and d)  2(3cyanopyridyl)  nbutyl  
D111 (a, b, c, and d)  2(3cyanopyridyl)  npropyl  
D112 (a, b, c, and d)  2(3cyanopyridyl)  isopropyl  
D113 (a, b, c, and d)  2(3bromopyridyl)  tertbutyl  
D114 (a, b, c, and d)  2(3bromopyridyl)  isobutyl  
D115 (a, b, c, and d)  2(3bromopyridyl)  secbutyl  
D116 (a, b, c, and d)  2(3bromopyridyl)  cyclohexyl  
D117 (a, b, c, and d)  2(3bromopyridyl)  tertbutoxy  
D118 (a, b, c, and d)  2(3bromopyridyl)  isopropoxy  
D119 (a, b, c, and d)  2(3bromopyridyl)  —CF_{3}  
D120 (a, b, c, and d)  2(3bromopyridyl)  —OCF_{3}  
D121 (a, b, c, and d)  2(3bromopyridyl)  —Cl  
D122 (a, b, c, and d)  2(3bromopyridyl)  —Br  
D123 (a, b, c, and d)  2(3bromopyridyl)  —I  
D124 (a, b, c, and d)  2(3bromopyridyl)  nbutyl  
D125 (a, b, c, and d)  2(3bromopyridyl)  npropyl  
D126 (a, b, c, and d)  2(3bromopyridyl)  isopropyl  
D127 (a, b, c, and d)  2(3iodopyridyl)  tertbutyl  
D128 (a, b, c, and d)  2(3iodopyridyl)  isobutyl  
D129 (a, b, c, and d)  2(3iodopyridyl)  secbutyl  
D130 (a, b, c, and d)  2(3iodopyridyl)  cyclohexyl  
D131 (a, b, c, and d)  2(3iodopyridyl)  tertbutoxy  
D132 (a, b, c, and d)  2(3iodopyridyl)  isopropoxy  
D133 (a, b, c, and d)  2(3iodopyridyl)  —CF_{3}  
D134 (a, b, c, and d)  2(3iodopyridyl)  —OCF_{3}  
D135 (a, b, c, and d)  2(3iodopyridyl)  —Cl  
D136 (a, b, c, and d)  2(3iodopyridyl)  —Br  
D137 (a, b, c, and d)  2(3iodopyridyl)  —I  
D138 (a, b, c, and d)  2(3iodopyridyl)  nbutyl  
D139 (a, b, c, and d)  2(3iodopyridyl)  npropyl  
D140 (a, b, c, and d)  2(3iodopyridyl)  isopropyl  
D141 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutyl  
D142 (a, b, c, and d)  4(5chloropyrimidinyl)  isobutyl  
D143 (a, b, c, and d)  4(5chloropyrimidinyl)  secbutyl  
D144 (a, b, c, and d)  4(5chloropyrimidinyl)  cyclohexyl  
D145 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutoxy  
D146 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropoxy  
D147 (a, b, c, and d)  4(5chloropyrimidinyl)  —CF_{3}  
D148 (a, b, c, and d)  4(5chloropyrimidinyl)  —OCF_{3}  
D149 (a, b, c, and d)  4(5chloropyrimidinyl)  —Cl  
D150 (a, b, c, and d)  4(5chloropyrimidinyl)  —Br  
D151 (a, b, c, and d)  4(5chloropyrimidinyl)  —I  
D152 (a, b, c, and d)  4(5chloropyrimidinyl)  nbutyl  
D153 (a, b, c, and d)  4(5chloropyrimidinyl)  npropyl  
D154 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropyl  
D155 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutyl  
D156 (a, b, c, and d)  4(5methylpyrimidinyl)  isobutyl  
D157 (a, b, c, and d)  4(5methylpyrimidinyl)  secbutyl  
D158 (a, b, c, and d)  4(5methylpyrimidinyl)  cyclohexyl  
D159 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutoxy  
D160 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropoxy  
D161 (a, b, c, and d)  4(5methylpyrimidinyl)  —CF_{3}  
D162 (a, b, c, and d)  4(5methylpyrimidinyl)  —OCF_{3}  
D163 (a, b, c, and d)  4(5methylpyrimidinyl)  —Cl  
D164 (a, b, c, and d)  4(5methylpyrimidinyl)  —Br  
D165 (a, b, c, and d)  4(5methylpyrimidinyl)  —I  
D166 (a, b, c, and d)  4(5methylpyrimidinyl)  nbutyl  
D167 (a, b, c, and d)  4(5methylpyrimidinyl)  npropyl  
D168 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropyl  
D169 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutyl  
D170 (a, b, c, and d)  4(5fluoropyrimidinyl)  isobutyl  
D171 (a, b, c, and d)  4(5fluoropyrimidinyl)  secbutyl  
D172 (a, b, c, and d)  4(5fluoropyrimidinyl)  cyclohexyl  
D173 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutoxy  
D174 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropoxy  
D175 (a, b, c, and d)  4(5fluoropyrimidinyl)  —CF_{3}  
D176 (a, b, c, and d)  4(5fluoropyrimidinyl)  —OCF_{3}  
D177 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Cl  
D178 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Br  
D179 (a, b, c, and d)  4(5fluoropyrimidinyl)  —I  
D180 (a, b, c, and d)  4(5fluoropyrimidinyl)  nbutyl  
D181 (a, b, c, and d)  4(5fluoropyrimidinyl)  npropyl  
D182 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropyl  
D183 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutyl  
D184 (a, b, c, and d)  2(3chloropyrazinyl)  isobutyl  
D185 (a, b, c, and d)  2(3chloropyrazinyl)  secbutyl  
D186 (a, b, c, and d)  2(3chloropyrazinyl)  cyclohexyl  
D187 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutoxy  
D188 (a, b, c, and d)  2(3chloropyrazinyl)  isopropoxy  
D189 (a, b, c, and d)  2(3chloropyrazinyl)  —CF_{3}  
D190 (a, b, c, and d)  2(3chloropyrazinyl)  —OCF_{3}  
D191 (a, b, c, and d)  2(3chloropyrazinyl)  —Cl  
D192 (a, b, c, and d)  2(3chloropyrazinyl)  —Br  
D193 (a, b, c, and d)  2(3chloropyrazinyl)  —I  
D194 (a, b, c, and d)  2(3chloropyrazinyl)  nbutyl  
D195 (a, b, c, and d)  2(3chloropyrazinyl)  npropyl  
D196 (a, b, c, and d)  2(3chloropyrazinyl)  isopropyl  
D197 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutyl  
D198 (a, b, c, and d)  2(3methylpyrazinyl)  isobutyl  
D199 (a, b, c, and d)  2(3methylpyrazinyl)  secbutyl  
D200 (a, b, c, and d)  2(3methylpyrazinyl)  cyclohexyl  
D201 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutoxy  
D202 (a, b, c, and d)  2(3methylpyrazinyl)  isopropoxy  
D203 (a, b, c, and d)  2(3methylpyrazinyl)  —CF_{3}  
D204 (a, b, c, and d)  2(3methylpyrazinyl)  —OCF_{3}  
D205 (a, b, c, and d)  2(3methylpyrazinyl)  —Cl  
D206 (a, b, c, and d)  2(3methylpyrazinyl)  —Br  
D207 (a, b, c, and d)  2(3methylpyrazinyl)  —I  
D208 (a, b, c, and d)  2(3methylpyrazinyl)  nbutyl  
D209 (a, b, c, and d)  2(3methylpyrazinyl)  npropyl  
D210 (a, b, c, and d)  2(3methylpyrazinyl)  isopropyl  
D211 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutyl  
D212 (a, b, c, and d)  2(3fluoropyrazinyl)  isobutyl  
D213 (a, b, c, and d)  2(3fluoropyrazinyl)  secbutyl  
D214 (a, b, c, and d)  2(3fluoropyrazinyl)  cyclohexyl  
D215 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutoxy  
D216 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropoxy  
D217 (a, b, c, and d)  2(3fluoropyrazinyl)  —CF_{3}  
D218 (a, b, c, and d)  2(3fluoropyrazinyl)  —OCF_{3}  
D219 (a, b, c, and d)  2(3fluoropyrazinyl)  —Cl  
D220 (a, b, c, and d)  2(3fluoropyrazinyl)  —Br  
D221 (a, b, c, and d)  2(3fluoropyrazinyl)  —I  
D222 (a, b, c, and d)  2(3fluoropyrazinyl)  nbutyl  
D223 (a, b, c, and d)  2(3fluoropyrazinyl)  npropyl  
D224 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropyl  
D225 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutyl  
D226 (a, b, c, and d)  3(4chloropyridazinyl)  isobutyl  
D227 (a, b, c, and d)  3(4chloropyridazinyl)  secbutyl  
D228 (a, b, c, and d)  3(4chloropyridazinyl)  cyclohexyl  
D229 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutoxy  
D230 (a, b, c, and d)  3(4chloropyridazinyl)  isopropoxy  
D231 (a, b, c, and d)  3(4chloropyridazinyl)  —CF_{3}  
D232 (a, b, c, and d)  3(4chloropyridazinyl)  —OCF_{3}  
D233 (a, b, c, and d)  3(4chloropyridazinyl)  —Cl  
D234 (a, b, c, and d)  3(4chloropyridazinyl)  —Br  
D235 (a, b, c, and d)  3(4chloropyridazinyl)  —I  
D236 (a, b, c, and d)  3(4chloropyridazinyl)  nbutyl  
D237 (a, b, c, and d)  3(4chloropyridazinyl)  npropyl  
D238 (a, b, c, and d)  3(4chloropyridazinyl)  isopropyl  
D239 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutyl  
D240 (a, b, c, and d)  3(4methylpyridazinyl)  isobutyl  
D241 (a, b, c, and d)  3(4methylpyridazinyl)  secbutyl  
D242 (a, b, c, and d)  3(4methylpyridazinyl)  cyclohexyl  
D243 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutoxy  
D244 (a, b, c, and d)  3(4methylpyridazinyl)  isopropoxy  
D245 (a, b, c, and d)  3(4methylpyridazinyl)  —CF_{3}  
D246 (a, b, c, and d)  3(4methylpyridazinyl)  —OCF_{3}  
D247 (a, b, c, and d)  3(4methylpyridazinyl)  —Cl  
D248 (a, b, c, and d)  3(4methylpyridazinyl)  —Br  
D249 (a, b, c, and d)  3(4methylpyridazinyl)  —I  
D250 (a, b, c, and d)  3(4methylpyridazinyl)  nbutyl  
D251 (a, b, c, and d)  3(4methylpyridazinyl)  npropyl  
D252 (a, b, c, and d)  3(4methylpyridazinyl)  isopropyl  
D253 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutyl  
D254 (a, b, c, and d)  3(4fluoropyridazinyl)  isobutyl  
D255 (a, b, c, and d)  3(4fluoropyridazinyl)  secbutyl  
D256 (a, b, c, and d)  3(4fluoropyridazinyl)  cyclohexyl  
D257 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutoxy  
D258 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropoxy  
D259 (a, b, c, and d)  3(4fluoropyridazinyl)  —CF_{3}  
D260 (a, b, c, and d)  3(4fluoropyridazinyl)  —OCF_{3}  
D261 (a, b, c, and d)  3(4fluoropyridazinyl)  —Cl  
D262 (a, b, c, and d)  3(4fluoropyridazinyl)  —Br  
D263 (a, b, c, and d)  3(4fluoropyridazinyl)  —I  
D264 (a, b, c, and d)  3(4fluoropyridazinyl)  nbutyl  
D265 (a, b, c, and d)  3(4fluoropyridazinyl)  npropyl  
D266 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropyl  
D267 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutyl  
D268 (a, b, c, and d)  5(4chlorothiadiazolyl)  isobutyl  
D269 (a, b, c, and d)  5(4chlorothiadiazolyl)  secbutyl  
D270 (a, b, c, and d)  5(4chlorothiadiazolyl)  cyclohexyl  
D271 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutoxy  
D272 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropoxy  
D273 (a, b, c, and d)  5(4chlorothiadiazolyl)  —CF_{3}  
D274 (a, b, c, and d)  5(4chlorothiadiazolyl)  —OCF_{3}  
D275 (a, b, c, and d)  5(4chlorothiadiazolyl)  —Cl  
D276 (a, b, c, and d)  5(4chlorothiadiazolyl)  —Br  
D277 (a, b, c, and d)  5(4chlorothiadiazolyl)  —I  
D278 (a, b, c, and d)  5(4chlorothiadiazolyl)  nbutyl  
D279 (a, b, c, and d)  5(4chlorothiadiazolyl)  npropyl  
D280 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropyl  
D281 (a, b, c, and d)  5(4methylthiadiazolyl)  tertbutyl  
D282 (a, b, c, and d)  5(4methylthiadiazolyl)  isobutyl  
D283 (a, b, c, and d)  5(4methylthiadiazolyl)  secbutyl  
D284 (a, b, c, and d)  5(4methylthiadiazolyl)  cyclohexyl  
D285 (a, b, c, and d)  5(4methylthiadiazolyl)  tertbutoxy  
D286 (a, b, c, and d)  5(4methylthiadiazolyl)  isopropoxy  
D287 (a, b, c, and d)  5(4methylthiadiazolyl)  —CF_{3}  
D288 (a, b, c, and d)  5(4methylthiadiazolyl)  —OCF_{3}  
D289 (a, b, c, and d)  5(4methylthiadiazolyl)  —Cl  
D290 (a, b, c, and d)  5(4methylthiadiazolyl)  —Br  
D291 (a, b, c, and d)  5(4methylthiadiazolyl)  —I  
D292 (a, b, c, and d)  5(4methylthiadiazolyl)  nbutyl  
D293 (a, b, c, and d)  5(4methylthiadiazolyl)  npropyl  
D294 (a, b, c, and d)  5(4methylthiadiazolyl)  isopropyl  
D295 (a, b, c, and d)  5(4fluorothiadiazolyl)  tertbutyl  
D296 (a, b, c, and d)  5(4fluorothiadiazolyl)  isobutyl  
D297 (a, b, c, and d)  5(4fluorothiadiazolyl)  secbutyl  
D298 (a, b, c, and d)  5(4fluorothiadiazolyl)  cyclohexyl  
D299 (a, b, c, and d)  5(4fluorothiadiazolyl)  tertbutoxy  
D300 (a, b, c, and d)  5(4fluorothiadiazolyl)  isopropoxy  
D301 (a, b, c, and d)  5(4fluorothiadiazolyl)  —CF_{3}  
D302 (a, b, c, and d)  5(4fluorothiadiazolyl)  —OCF_{3}  
D303 (a, b, c, and d)  5(4fluorothiadiazolyl)  —Cl  
D304 (a, b, c, and d)  5(4fluorothiadiazolyl)  —Br  
D305 (a, b, c, and d)  5(4fluorothiadiazolyl)  —I  
D306 (a, b, c, and d)  5(4fluorothiadiazolyl)  nbutyl  
D307 (a, b, c, and d)  5(4fluorothiadiazolyl)  npropyl  
D308 (a, b, c, and d)  5(4fluorothiadiazolyl)  isopropyl  
“a” means R_{3 }is —H.  
“b” means R_{3 }is —CH_{3 }and the Nitro(cyano)vinylpiperazine Compound is racemic.  
“c” means R_{3 }is —CH_{3 }and the carbon atom to which R_{3 }is attached is in the (R) configuration.  
“d” means R_{3 }is —CH_{3 }and the carbon atom to which R_{3 }is attached is in the (S) configuration. 
TABLE 5  
(VII)  


and pharmaceutically acceptable salts thereof, where:  
Compound  Ar_{1}  R_{8a}  
E1 (a, b, c, and d)  2(3chloropyridyl)  tertbutyl  
E2 (a, b, c, and d)  2(3chloropyridyl)  isobutyl  
E3 (a, b, c, and d)  2(3chloropyridyl)  secbutyl  
E4 (a, b, c, and d)  2(3chloropyridyl)  cyclohexyl  
E5 (a, b, c, and d)  2(3chloropyridyl)  tertbutoxy  
E6 (a, b, c, and d)  2(3chloropyridyl)  isopropoxy  
E7 (a, b, c, and d)  2(3chloropyridyl)  —CF_{3}  
E8 (a, b, c, and d)  2(3chloropyridyl)  —OCF_{3}  
E9 (a, b, c, and d)  2(3chloropyridyl)  —Cl  
E10 (a, b, c, and d)  2(3chloropyridyl)  —Br  
E11 (a, b, c, and d)  2(3chloropyridyl)  —I  
E12 (a, b, c, and d)  2(3chloropyridyl)  nbutyl  
E13 (a, b, c, and d)  2(3chloropyridyl)  npropyl  
E14 (a, b, c, and d)  2(3chloropyridyl)  isopropyl  
E15 (a, b, c, and d)  2(3fluoropyridyl)  tertbutyl  
E16 (a, b, c, and d)  2(3fluoropyridyl)  isobutyl  
E17 (a, b, c, and d)  2(3fluoropyridyl)  secbutyl  
E18 (a, b, c, and d)  2(3fluoropyridyl)  cyclohexyl  
E19 (a, b, c, and d)  2(3fluoropyridyl)  tertbutoxy  
E20 (a, b, c, and d)  2(3fluoropyridyl)  isopropoxy  
E21 (a, b, c, and d)  2(3fluoropyridyl)  —CF_{3}  
E22 (a, b, c, and d)  2(3fluoropyridyl)  —OCF_{3}  
E23 (a, b, c, and d)  2(3fluoropyridyl)  —Cl  
E24 (a, b, c, and d)  2(3fluoropyridyl)  —Br  
E25 (a, b, c, and d)  2(3fluoropyridyl)  —I  
E26 (a, b, c, and d)  2(3fluoropyridyl)  nbutyl  
E27 (a, b, c, and d)  2(3fluoropyridyl)  npropyl  
E28 (a, b, c, and d)  2(3fluoropyridyl)  isopropyl  
E29 (a, b, c, and d)  2(3methylpyridyl)  tertbutyl  
E30 (a, b, c, and d)  2(3methylpyridyl)  isobutyl  
E31 (a, b, c, and d)  2(3methylpyridyl)  secbutyl  
E32 (a, b, c, and d)  2(3methylpyridyl)  cyclohexyl  
E33 (a, b, c, and d)  2(3methylpyridyl)  tertbutoxy  
E34 (a, b, c, and d)  2(3methylpyridyl)  isopropoxy  
E35 (a, b, c, and d)  2(3methylpyridyl)  —CF_{3}  
E36 (a, b, c, and d)  2(3methylpyridyl)  —OCF_{3}  
E37 (a, b, c, and d)  2(3methylpyridyl)  —Cl  
E38 (a, b, c, and d)  2(3methylpyridyl)  —Br  
E39 (a, b, c, and d)  2(3methylpyridyl)  —I  
E40 (a, b, c, and d)  2(3methylpyridyl)  nbutyl  
E41 (a, b, c, and d)  2(3methylpyridyl)  npropyl  
E42 (a, b, c, and d)  2(3methylpyridyl)  isopropyl  
E43 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutyl  
E44 (a, b, c, and d)  2(3CF_{3}pyridyl)  isobutyl  
E45 (a, b, c, and d)  2(3CF_{3}pyridyl)  secbutyl  
E46 (a, b, c, and d)  2(3CF_{3}pyridyl)  cyclohexyl  
E47 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutoxy  
E48 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropoxy  
E49 (a, b, c, and d)  2(3CF_{3}pyridyl)  —CF_{3}  
E50 (a, b, c, and d)  2(3CF_{3}pyridyl)  —OCF_{3}  
E51 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Cl  
E52 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Br  
E53 (a, b, c, and d)  2(3CF_{3}pyridyl)  —I  
E54 (a, b, c, and d)  2(3CF_{3}pyridyl)  nbutyl  
E55 (a, b, c, and d)  2(3CF_{3}pyridyl)  npropyl  
E56 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropyl  
E57 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutyl  
E58 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isobutyl  
E59 (a, b, c, and d)  2(3CHF_{2}pyridyl)  secbutyl  
E60 (a, b, c, and d)  2(3CHF_{2}pyridyl)  cyclohexyl  
E61 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutoxy  
E62 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropoxy  
E63 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —CF_{3}  
E64 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —OCF_{3}  
E65 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Cl  
E66 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Br  
E67 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —I  
E68 (a, b, c, and d)  2(3CHF_{2}pyridyl)  nbutyl  
E69 (a, b, c, and d)  2(3CHF_{2}pyridyl)  npropyl  
E70 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropyl  
E71 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutyl  
E72 (a, b, c, and d)  2(3hydroxypyridyl)  isobutyl  
E73 (a, b, c, and d)  2(3hydroxypyridyl)  secbutyl  
E74 (a, b, c, and d)  2(3hydroxypyridyl)  cyclohexyl  
E75 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutoxy  
E76 (a, b, c, and d)  2(3hydroxypyridyl)  isopropoxy  
E77 (a, b, c, and d)  2(3hydroxypyridyl)  —CF_{3}  
E78 (a, b, c, and d)  2(3hydroxypyridyl)  —OCF_{3}  
E79 (a, b, c, and d)  2(3hydroxypyridyl)  —Cl  
E80 (a, b, c, and d)  2(3hydroxypyridyl)  —Br  
E81 (a, b, c, and d)  2(3hydroxypyridyl)  —I  
E82 (a, b, c, and d)  2(3hydroxypyridyl)  nbutyl  
E83 (a, b, c, and d)  2(3hydroxypyridyl)  npropyl  
E84 (a, b, c, and d)  2(3hydroxypyridyl)  isopropyl  
E85 (a, b, c, and d)  2(3nitropyridyl)  tertbutyl  
E86 (a, b, c, and d)  2(3nitropyridyl)  isobutyl  
E87 (a, b, c, and d)  2(3nitropyridyl)  secbutyl  
E88 (a, b, c, and d)  2(3nitropyridyl)  cyclohexyl  
E89 (a, b, c, and d)  2(3nitropyridyl)  tertbutoxy  
E90 (a, b, c, and d)  2(3nitropyridyl)  isopropoxy  
E91 (a, b, c, and d)  2(3nitropyridyl)  —CF_{3}  
E92 (a, b, c, and d)  2(3nitropyridyl)  —OCF_{3}  
E93 (a, b, c, and d)  2(3nitropyridyl)  —Cl  
E94 (a, b, c, and d)  2(3nitropyridyl)  —Br  
E95 (a, b, c, and d)  2(3nitropyridyl)  —I  
E96 (a, b, c, and d)  2(3nitropyridyl)  nbutyl  
E97 (a, b, c, and d)  2(3nitropyridyl)  npropyl  
E98 (a, b, c, and d)  2(3nitropyridyl)  isopropyl  
E99 (a, b, c, and d)  2(3cyanopyridyl)  tertbutyl  
E100 (a, b, c, and d)  2(3cyanopyridyl)  isobutyl  
E101 (a, b, c, and d)  2(3cyanopyridyl)  secbutyl  
E102 (a, b, c, and d)  2(3cyanopyridyl)  cyclohexyl  
E103 (a, b, c, and d)  2(3cyanopyridyl)  tertbutoxy  
E104 (a, b, c, and d)  2(3cyanopyridyl)  isopropoxy  
E105 (a, b, c, and d)  2(3cyanopyridyl)  —CF_{3}  
E106 (a, b, c, and d)  2(3cyanopyridyl)  —OCF_{3}  
E107 (a, b, c, and d)  2(3cyanopyridyl)  —Cl  
E108 (a, b, c, and d)  2(3cyanopyridyl)  —Br  
E109 (a, b, c, and d)  2(3cyanopyridyl)  —I  
E110 (a, b, c, and d)  2(3cyanopyridyl)  nbutyl  
E111 (a, b, c, and d)  2(3cyanopyridyl)  npropyl  
E112 (a, b, c, and d)  2(3cyanopyridyl)  isopropyl  
E113 (a, b, c, and d)  2(3bromopyridyl)  tertbutyl  
E114 (a, b, c, and d)  2(3bromopyridyl)  isobutyl  
E115 (a, b, c, and d)  2(3bromopyridyl)  secbutyl  
E116 (a, b, c, and d)  2(3bromopyridyl)  cyclohexyl  
E117 (a, b, c, and d)  2(3bromopyridyl)  tertbutoxy  
E118 (a, b, c, and d)  2(3bromopyridyl)  isopropoxy  
E119 (a, b, c, and d)  2(3bromopyridyl)  —CF_{3}  
E120 (a, b, c, and d)  2(3bromopyridyl)  —OCF_{3}  
E121 (a, b, c, and d)  2(3bromopyridyl)  —Cl  
E122 (a, b, c, and d)  2(3bromopyridyl)  —Br  
E123 (a, b, c, and d)  2(3bromopyridyl)  —I  
E124 (a, b, c, and d)  2(3bromopyridyl)  nbutyl  
E125 (a, b, c, and d)  2(3bromopyridyl)  npropyl  
E126 (a, b, c, and d)  2(3bromopyridyl)  isopropyl  
E127 (a, b, c, and d)  2(3iodopyridyl)  tertbutyl  
E128 (a, b, c, and d)  2(3iodopyridyl)  isobutyl  
E129 (a, b, c, and d)  2(3iodopyridyl)  secbutyl  
E130 (a, b, c, and d)  2(3iodopyridyl)  cyclohexyl  
E131 (a, b, c, and d)  2(3iodopyridyl)  tertbutoxy  
E132 (a, b, c, and d)  2(3iodopyridyl)  isopropoxy  
E133 (a, b, c, and d)  2(3iodopyridyl)  —CF_{3}  
E134 (a, b, c, and d)  2(3iodopyridyl)  —OCF_{3}  
E135 (a, b, c, and d)  2(3iodopyridyl)  —Cl  
E136 (a, b, c, and d)  2(3iodopyridyl)  —Br  
E137 (a, b, c, and d)  2(3iodopyridyl)  —I  
E138 (a, b, c, and d)  2(3iodopyridyl)  nbutyl  
E139 (a, b, c, and d)  2(3iodopyridyl)  npropyl  
E140 (a, b, c, and d)  2(3iodopyridyl)  isopropyl  
E141 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutyl  
E142 (a, b, c, and d)  4(5chloropyrimidinyl)  isobutyl  
E143 (a, b, c, and d)  4(5chloropyrimidinyl)  secbutyl  
E144 (a, b, c, and d)  4(5chloropyrimidinyl)  cyclohexyl  
E145 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutoxy  
E146 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropoxy  
E147 (a, b, c, and d)  4(5chloropyrimidinyl)  —CF_{3}  
E148 (a, b, c, and d)  4(5chloropyrimidinyl)  —OCF_{3}  
E149 (a, b, c, and d)  4(5chloropyrimidinyl)  —Cl  
E150 (a, b, c, and d)  4(5chloropyrimidinyl)  —Br  
E151 (a, b, c, and d)  4(5chloropyrimidinyl)  —I  
E152 (a, b, c, and d)  4(5chloropyrimidinyl)  nbutyl  
E153 (a, b, c, and d)  4(5chloropyrimidinyl)  npropyl  
E154 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropyl  
E155 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutyl  
E156 (a, b, c, and d)  4(5methylpyrimidinyl)  isobutyl  
E157 (a, b, c, and d)  4(5methylpyrimidinyl)  secbutyl  
E158 (a, b, c, and d)  4(5methylpyrimidinyl)  cyclohexyl  
E159 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutoxy  
E160 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropoxy  
E161 (a, b, c, and d)  4(5methylpyrimidinyl)  —CF_{3}  
E162 (a, b, c, and d)  4(5methylpyrimidinyl)  —OCF_{3}  
E163 (a, b, c, and d)  4(5methylpyrimidinyl)  —Cl  
E164 (a, b, c, and d)  4(5methylpyrimidinyl)  —Br  
E165 (a, b, c, and d)  4(5methylpyrimidinyl)  —I  
E166 (a, b, c, and d)  4(5methylpyrimidinyl)  nbutyl  
E167 (a, b, c, and d)  4(5methylpyrimidinyl)  npropyl  
E168 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropyl  
E169 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutyl  
E170 (a, b, c, and d)  4(5fluoropyrimidinyl)  isobutyl  
E171 (a, b, c, and d)  4(5fluoropyrimidinyl)  secbutyl  
E172 (a, b, c, and d)  4(5fluoropyrimidinyl)  cyclohexyl  
E173 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutoxy  
E174 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropoxy  
E175 (a, b, c, and d)  4(5fluoropyrimidinyl)  —CF_{3}  
E176 (a, b, c, and d)  4(5fluoropyrimidinyl)  —OCF_{3}  
E177 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Cl  
E178 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Br  
E179 (a, b, c, and d)  4(5fluoropyrimidinyl)  —I  
E180 (a, b, c, and d)  4(5fluoropyrimidinyl)  nbutyl  
E181 (a, b, c, and d)  4(5fluoropyrimidinyl)  npropyl  
E182 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropyl  
E183 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutyl  
E184 (a, b, c, and d)  2(3chloropyrazinyl)  isobutyl  
E185 (a, b, c, and d)  2(3chloropyrazinyl)  secbutyl  
E186 (a, b, c, and d)  2(3chloropyrazinyl)  cyclohexyl  
E187 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutoxy  
E188 (a, b, c, and d)  2(3chloropyrazinyl)  isopropoxy  
E189 (a, b, c, and d)  2(3chloropyrazinyl)  —CF_{3}  
E190 (a, b, c, and d)  2(3chloropyrazinyl)  —OCF_{3}  
E191 (a, b, c, and d)  2(3chloropyrazinyl)  —Cl  
E192 (a, b, c, and d)  2(3chloropyrazinyl)  —Br  
E193 (a, b, c, and d)  2(3chloropyrazinyl)  —I  
E194 (a, b, c, and d)  2(3chloropyrazinyl)  nbutyl  
E195 (a, b, c, and d)  2(3chloropyrazinyl)  npropyl  
E196 (a, b, c, and d)  2(3chloropyrazinyl)  isopropyl  
E197 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutyl  
E198 (a, b, c, and d)  2(3methylpyrazinyl)  isobutyl  
E199 (a, b, c, and d)  2(3methylpyrazinyl)  secbutyl  
E200 (a, b, c, and d)  2(3methylpyrazinyl)  cyclohexyl  
E201 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutoxy  
E202 (a, b, c, and d)  2(3methylpyrazinyl)  isopropoxy  
E203 (a, b, c, and d)  2(3methylpyrazinyl)  —CF_{3}  
E204 (a, b, c, and d)  2(3methylpyrazinyl)  —OCF_{3}  
E205 (a, b, c, and d)  2(3methylpyrazinyl)  —Cl  
E206 (a, b, c, and d)  2(3methylpyrazinyl)  —Br  
E207 (a, b, c, and d)  2(3methylpyrazinyl)  —I  
E208 (a, b, c, and d)  2(3methylpyrazinyl)  nbutyl  
E209 (a, b, c, and d)  2(3methylpyrazinyl)  npropyl  
E210 (a, b, c, and d)  2(3methylpyrazinyl)  isopropyl  
E211 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutyl  
E212 (a, b, c, and d)  2(3fluoropyrazinyl)  isobutyl  
E213 (a, b, c, and d)  2(3fluoropyrazinyl)  secbutyl  
E214 (a, b, c, and d)  2(3fluoropyrazinyl)  cyclohexyl  
E215 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutoxy  
E216 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropoxy  
E217 (a, b, c, and d)  2(3fluoropyrazinyl)  —CF_{3}  
E218 (a, b, c, and d)  2(3fluoropyrazinyl)  —OCF_{3}  
E219 (a, b, c, and d)  2(3fluoropyrazinyl)  —Cl  
E220 (a, b, c, and d)  2(3fluoropyrazinyl)  —Br  
E221 (a, b, c, and d)  2(3fluoropyrazinyl)  —I  
E222 (a, b, c, and d)  2(3fluoropyrazinyl)  nbutyl  
E223 (a, b, c, and d)  2(3fluoropyrazinyl)  npropyl  
E224 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropyl  
E225 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutyl  
E226 (a, b, c, and d)  3(4chloropyridazinyl)  isobutyl  
E227 (a, b, c, and d)  3(4chloropyridazinyl)  secbutyl  
E228 (a, b, c, and d)  3(4chloropyridazinyl)  cyclohexyl  
E229 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutoxy  
E230 (a, b, c, and d)  3(4chloropyridazinyl)  isopropoxy  
E231 (a, b, c, and d)  3(4chloropyridazinyl)  —CF_{3}  
E232 (a, b, c, and d)  3(4chloropyridazinyl)  —OCF_{3}  
E233 (a, b, c, and d)  3(4chloropyridazinyl)  —Cl  
E234 (a, b, c, and d)  3(4chloropyridazinyl)  —Br  
E235 (a, b, c, and d)  3(4chloropyridazinyl)  —I  
E236 (a, b, c, and d)  3(4chloropyridazinyl)  nbutyl  
E237 (a, b, c, and d)  3(4chloropyridazinyl)  npropyl  
E238 (a, b, c, and d)  3(4chloropyridazinyl)  isopropyl  
E239 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutyl  
E240 (a, b, c, and d)  3(4methylpyridazinyl)  isobutyl  
E241 (a, b, c, and d)  3(4methylpyridazinyl)  secbutyl  
E242 (a, b, c, and d)  3(4methylpyridazinyl)  cyclohexyl  
E243 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutoxy  
E244 (a, b, c, and d)  3(4methylpyridazinyl)  isopropoxy  
E245 (a, b, c, and d)  3(4methylpyridazinyl)  —CF_{3}  
E246 (a, b, c, and d)  3(4methylpyridazinyl)  —OCF_{3}  
E247 (a, b, c, and d)  3(4methylpyridazinyl)  —Cl  
E248 (a, b, c, and d)  3(4methylpyridazinyl)  —Br  
E249 (a, b, c, and d)  3(4methylpyridazinyl)  —I  
E250 (a, b, c, and d)  3(4methylpyridazinyl)  nbutyl  
E251 (a, b, c, and d)  3(4methylpyridazinyl)  npropyl  
E252 (a, b, c, and d)  3(4methylpyridazinyl)  isopropyl  
E253 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutyl  
E254 (a, b, c, and d)  3(4fluoropyridazinyl)  isobutyl  
E255 (a, b, c, and d)  3(4fluoropyridazinyl)  secbutyl  
E256 (a, b, c, and d)  3(4fluoropyridazinyl)  cyclohexyl  
E257 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutoxy  
E258 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropoxy  
E259 (a, b, c, and d)  3(4fluoropyridazinyl)  —CF_{3}  
E260 (a, b, c, and d)  3(4fluoropyridazinyl)  —OCF_{3}  
E261 (a, b, c, and d)  3(4fluoropyridazinyl)  —Cl  
E262 (a, b, c, and d)  3(4fluoropyridazinyl)  —Br  
E263 (a, b, c, and d)  3(4fluoropyridazinyl)  —I  
E264 (a, b, c, and d)  3(4fluoropyridazinyl)  nbutyl  
E265 (a, b, c, and d)  3(4fluoropyridazinyl)  npropyl  
E266 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropyl  
E267 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutyl  
E268 (a, b, c, and d)  5(4chlorothiadiazolyl)  isobutyl  
E269 (a, b, c, and d)  5(4chlorothiadiazolyl)  secbutyl  
E270 (a, b, c, and d)  5(4chlorothiadiazolyl)  cyclohexyl  
E271 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutoxy  
E272 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropoxy  
E273 (a, b, c, and d)  5(4chlorothiadiazolyl)  —CF_{3}  
E274 (a, b, c, and d)  5(4chlorothiadiazolyl)  —OCF_{3}  
E275 (a, b, c, and d)  5(4chlorothiadiazolyl)  —Cl  
E276 (a, b, c, and d)  5(4chlorothiadiazolyl)  —Br  
E277 (a, b, c, and d)  5(4chlorothiadiazolyl)  —I  
E278 (a, b, c, and d)  5(4chlorothiadiazolyl)  nbutyl  
E279 (a, b, c, and d)  5(4chlorothiadiazolyl)  npropyl  
E280 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropyl  
E281 (a, b, c, and d)  5(4methylthiadiazolyl)  tertbutyl  
E282 (a, b, c, and d)  5(4methylthiadiazolyl)  isobutyl  
E283 (a, b, c, and d)  5(4methylthiadiazolyl)  secbutyl  
E284 (a, b, c, and d)  5(4methylthiadiazolyl)  cyclohexyl  
E285 (a, b, c, and d)  5(4methylthiadiazolyl)  tertbutoxy  
E286 (a, b, c, and d)  5(4methylthiadiazolyl)  isopropoxy  
E287 (a, b, c, and d)  5(4methylthiadiazolyl)  —CF_{3}  
E288 (a, b, c, and d)  5(4methylthiadiazolyl)  —OCF_{3}  
E289 (a, b, c, and d)  5(4methylthiadiazolyl)  —Cl  
E290 (a, b, c, and d)  5(4methylthiadiazolyl)  —Br  
E291 (a, b, c, and d)  5(4methylthiadiazolyl)  —I  
E292 (a, b, c, and d)  5(4methylthiadiazolyl)  nbutyl  
E293 (a, b, c, and d)  5(4methylthiadiazolyl)  npropyl  
E294 (a, b, c, and d)  5(4methylthiadiazolyl)  isopropyl  
E295 (a, b, c, and d)  5(4fluorothiadiazolyl)  tertbutyl  
E296 (a, b, c, and d)  5(4fluorothiadiazolyl)  isobutyl  
E297 (a, b, c, and d)  5(4fluorothiadiazolyl)  secbutyl  
E298 (a, b, c, and d)  5(4fluorothiadiazolyl)  cyclohexyl  
E299 (a, b, c, and d)  5(4fluorothiadiazolyl)  tertbutoxy  
E300 (a, b, c, and d)  5(4fluorothiadiazolyl)  isopropoxy  
E301 (a, b, c, and d)  5(4fluorothiadiazolyl)  —CF_{3}  
E302 (a, b, c, and d)  5(4fluorothiadiazolyl)  —OCF_{3}  
E303 (a, b, c, and d)  5(4fluorothiadiazolyl)  —Cl  
E304 (a, b, c, and d)  5(4fluorothiadiazolyl)  —Br  
E305 (a, b, c, and d)  5(4fluorothiadiazolyl)  —I  
E306 (a, b, c, and d)  5(4fluorothiadiazolyl)  nbutyl  
E307 (a, b, c, and d)  5(4fluorothiadiazolyl)  npropyl  
E308 (a, b, c, and d)  5(4fluorothiadiazolyl)  isopropyl  
“a” means R_{3 }is —H.  
“b” means R_{3 }is —CH_{3 }and the Nitro(cyano)vinylpiperazine Compound is racemic.  
“c” means R_{3 }is —CH_{3 }and the carbon atom to which R_{3 }is attached is in the (R) configuration.  
“d” means R_{3 }is —CH_{3 }and the carbon atom to which R_{3 }is attached is in the (S) configuration. 
TABLE 6  
(VIII)  


and pharmaceutically acceptable salts thereof, where:  
Compound  Ar_{1}  R_{8a}  
F1(a, b, c, and d)  2(3chloropyridyl)  tertbutyl  
F2 (a, b, c, and d)  2(3chloropyridyl)  isobutyl  
F3 (a, b, c, and d)  2(3chloropyridyl)  secbutyl  
F4 (a, b, c, and d)  2(3chloropyridyl)  cyclohexyl  
F5 (a, b, c, and d)  2(3chloropyridyl)  tertbutoxy  
F6 (a, b, c, and d)  2(3chloropyridyl)  isopropoxy  
F7 (a, b, c, and d)  2(3chloropyridyl)  —CF_{3}  
F8 (a, b, c, and d)  2(3chloropyridyl)  —OCF_{3}  
F9 (a, b, c, and d)  2(3chloropyridyl)  —Cl  
F10 (a, b, c, and d)  2(3chloropyridyl)  —Br  
F11 (a, b, c, and d)  2(3chloropyridyl)  —I  
F12 (a, b, c, and d)  2(3chloropyridyl)  nbutyl  
F13 (a, b, c, and d)  2(3chloropyridyl)  npropyl  
F14 (a, b, c, and d)  2(3chloropyridyl)  isopropyl  
F15 (a, b, c, and d)  2(3fluoropyridyl)  tertbutyl  
F16 (a, b, c, and d)  2(3fluoropyridyl)  isobutyl  
F17 (a, b, c, and d)  2(3fluoropyridyl)  secbutyl  
F18 (a, b, c, and d)  2(3fluoropyridyl)  cyclohexyl  
F19 (a, b, c, and d)  2(3fluoropyridyl)  tertbutoxy  
F20 (a, b, c, and d)  2(3fluoropyridyl)  isopropoxy  
F21 (a, b, c, and d)  2(3fluoropyridyl)  —CF_{3}  
F22 (a, b, c, and d)  2(3fluoropyridyl)  —OCF_{3}  
F23 (a, b, c, and d)  2(3fluoropyridyl)  —Cl  
F24 (a, b, c, and d)  2(3fluoropyridyl)  —Br  
F25 (a, b, c, and d)  2(3fluoropyridyl)  —I  
F26 (a, b, c, and d)  2(3fluoropyridyl)  nbutyl  
F27 (a, b, c, and d)  2(3fluoropyridyl)  npropyl  
F28 (a, b, c, and d)  2(3fluoropyridyl)  isopropyl  
F29 (a, b, c, and d)  2(3methylpyridyl)  tertbutyl  
F30 (a, b, c, and d)  2(3methylpyridyl)  isobutyl  
F31 (a, b, c, and d)  2(3methylpyridyl)  secbutyl  
F32 (a, b, c, and d)  2(3methylpyridyl)  cyclohexyl  
F33 (a, b, c, and d)  2(3methylpyridyl)  tertbutoxy  
F34 (a, b, c, and d)  2(3methylpyridyl)  isopropoxy  
F35 (a, b, c, and d)  2(3methylpyridyl)  —CF_{3}  
F36 (a, b, c, and d)  2(3methylpyridyl)  —OCF_{3}  
F37 (a, b, c, and d)  2(3methylpyridyl)  —Cl  
F38 (a, b, c, and d)  2(3methylpyridyl)  —Br  
F39 (a, b, c, and d)  2(3methylpyridyl)  —I  
F40 (a, b, c, and d)  2(3methylpyridyl)  nbutyl  
F41 (a, b, c, and d)  2(3methylpyridyl)  npropyl  
F42 (a, b, c, and d)  2(3methylpyridyl)  isopropyl  
F43 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutyl  
F44 (a, b, c, and d)  2(3CF_{3}pyridyl)  isobutyl  
F45 (a, b, c, and d)  2(3CF_{3}pyridyl)  secbutyl  
F46 (a, b, c, and d)  2(3CF_{3}pyridyl)  cyclohexyl  
F47 (a, b, c, and d)  2(3CF_{3}pyridyl)  tertbutoxy  
F48 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropoxy  
F49 (a, b, c, and d)  2(3CF_{3}pyridyl)  —CF_{3}  
F50 (a, b, c, and d)  2(3CF_{3}pyridyl)  —OCF_{3}  
F51 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Cl  
F52 (a, b, c, and d)  2(3CF_{3}pyridyl)  —Br  
F53 (a, b, c, and d)  2(3CF_{3}pyridyl)  —I  
F54 (a, b, c, and d)  2(3CF_{3}pyridyl)  nbutyl  
F55 (a, b, c, and d)  2(3CF_{3}pyridyl)  npropyl  
F56 (a, b, c, and d)  2(3CF_{3}pyridyl)  isopropyl  
F57 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutyl  
F58 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isobutyl  
F59 (a, b, c, and d)  2(3CHF_{2}pyridyl)  secbutyl  
F60 (a, b, c, and d)  2(3CHF_{2}pyridyl)  cyclohexyl  
F61 (a, b, c, and d)  2(3CHF_{2}pyridyl)  tertbutoxy  
F62 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropoxy  
F63 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —CF_{3}  
F64 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —OCF_{3}  
F65 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Cl  
F66 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —Br  
F67 (a, b, c, and d)  2(3CHF_{2}pyridyl)  —I  
F68 (a, b, c, and d)  2(3CHF_{2}pyridyl)  nbutyl  
F69 (a, b, c, and d)  2(3CHF_{2}pyridyl)  npropyl  
F70 (a, b, c, and d)  2(3CHF_{2}pyridyl)  isopropyl  
F71 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutyl  
F72 (a, b, c, and d)  2(3hydroxypyridyl)  isobutyl  
F73 (a, b, c, and d)  2(3hydroxypyridyl)  secbutyl  
F74 (a, b, c, and d)  2(3hydroxypyridyl)  cyclohexyl  
F75 (a, b, c, and d)  2(3hydroxypyridyl)  tertbutoxy  
F76 (a, b, c, and d)  2(3hydroxypyridyl)  isopropoxy  
F77 (a, b, c, and d)  2(3hydroxypyridyl)  —CF_{3}  
F78 (a, b, c, and d)  2(3hydroxypyridyl)  —OCF_{3}  
F79 (a, b, c, and d)  2(3hydroxypyridyl)  —Cl  
F80 (a, b, c, and d)  2(3hydroxypyridyl)  —Br  
F81 (a, b, c, and d)  2(3hydroxypyridyl)  —I  
F82 (a, b, c, and d)  2(3hydroxypyridyl)  nbutyl  
F83 (a, b, c, and d)  2(3hydroxypyridyl)  npropyl  
F84 (a, b, c, and d)  2(3hydroxypyridyl)  isopropyl  
F85 (a, b, c, and d)  2(3nitropyridyl)  tertbutyl  
F86 (a, b, c, and d)  2(3nitropyridyl)  isobutyl  
F87 (a, b, c, and d)  2(3nitropyridyl)  secbutyl  
F88 (a, b, c, and d)  2(3nitropyridyl)  cyclohexyl  
F89 (a, b, c, and d)  2(3nitropyridyl)  tertbutoxy  
F90 (a, b, c, and d)  2(3nitropyridyl)  isopropoxy  
F91 (a, b, c, and d)  2(3nitropyridyl)  —CF_{3}  
F92 (a, b, c, and d)  2(3nitropyridyl)  —OCF_{3}  
F93 (a, b, c, and d)  2(3nitropyridyl)  —Cl  
F94 (a, b, c, and d)  2(3nitropyridyl)  —Br  
F95 (a, b, c, and d)  2(3nitropyridyl)  —I  
F96 (a, b, c, and d)  2(3nitropyridyl)  nbutyl  
F97 (a, b, c, and d)  2(3nitropyridyl)  npropyl  
F98 (a, b, c, and d)  2(3nitropyridyl)  isopropyl  
F99 (a, b, c, and d)  2(3cyanopyridyl)  tertbutyl  
F100 (a, b, c, and d)  2(3cyanopyridyl)  isobutyl  
F101 (a, b, c, and d)  2(3cyanopyridyl)  secbutyl  
F102 (a, b, c, and d)  2(3cyanopyridyl)  cyclohexyl  
F103 (a, b, c, and d)  2(3cyanopyridyl)  tertbutoxy  
F104 (a, b, c, and d)  2(3cyanopyridyl)  isopropoxy  
F105 (a, b, c, and d)  2(3cyanopyridyl)  —CF_{3}  
F106 (a, b, c, and d)  2(3cyanopyridyl)  —OCF_{3}  
F107 (a, b, c, and d)  2(3cyanopyridyl)  —Cl  
F108 (a, b, c, and d)  2(3cyanopyridyl)  —Br  
F109 (a, b, c, and d)  2(3cyanopyridyl)  —I  
F110 (a, b, c, and d)  2(3cyanopyridyl)  nbutyl  
F111 (a, b, c, and d)  2(3cyanopyridyl)  npropyl  
F112 (a, b, c, and d)  2(3cyanopyridyl)  isopropyl  
F113 (a, b, c, and d)  2(3bromopyridyl)  tertbutyl  
F114 (a, b, c, and d)  2(3bromopyridyl)  isobutyl  
F115 (a, b, c, and d)  2(3bromopyridyl)  secbutyl  
F116 (a, b, c, and d)  2(3bromopyridyl)  cyclohexyl  
F117 (a, b, c, and d)  2(3bromopyridyl)  tertbutoxy  
F118 (a, b, c, and d)  2(3bromopyridyl)  isopropoxy  
F119 (a, b, c, and d)  2(3bromopyridyl)  —CF_{3}  
F120 (a, b, c, and d)  2(3bromopyridyl)  —OCF_{3}  
F121 (a, b, c, and d)  2(3bromopyridyl)  —Cl  
F122 (a, b, c, and d)  2(3bromopyridyl)  —Br  
F123 (a, b, c, and d)  2(3bromopyridyl)  —I  
F124 (a, b, c, and d)  2(3bromopyridyl)  nbutyl  
F125 (a, b, c, and d)  2(3bromopyridyl)  npropyl  
F126 (a, b, c, and d)  2(3bromopyridyl)  isopropyl  
F127 (a, b, c, and d)  2(3iodopyridyl)  tertbutyl  
F128 (a, b, c, and d)  2(3iodopyridyl)  isobutyl  
F129 (a, b, c, and d)  2(3iodopyridyl)  secbutyl  
F130 (a, b, c, and d)  2(3iodopyridyl)  cyclohexyl  
F131 (a, b, c, and d)  2(3iodopyridyl)  tertbutoxy  
F132 (a, b, c, and d)  2(3iodopyridyl)  isopropoxy  
F133 (a, b, c, and d)  2(3iodopyridyl)  —CF_{3}  
F134 (a, b, c, and d)  2(3iodopyridyl)  —OCF_{3}  
F135 (a, b, c, and d)  2(3iodopyridyl)  —Cl  
F136 (a, b, c, and d)  2(3iodopyridyl)  —Br  
F137 (a, b, c, and d)  2(3iodopyridyl)  —I  
F138 (a, b, c, and d)  2(3iodopyridyl)  nbutyl  
F139 (a, b, c, and d)  2(3iodopyridyl)  npropyl  
F140 (a, b, c, and d)  2(3iodopyridyl)  isopropyl  
F141 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutyl  
F142 (a, b, c, and d)  4(5chloropyrimidinyl)  isobutyl  
F143 (a, b, c, and d)  4(5chloropyrimidinyl)  secbutyl  
F144 (a, b, c, and d)  4(5chloropyrimidinyl)  cyclohexyl  
F145 (a, b, c, and d)  4(5chloropyrimidinyl)  tertbutoxy  
F146 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropoxy  
F147 (a, b, c, and d)  4(5chloropyrimidinyl)  —CF_{3}  
F148 (a, b, c, and d)  4(5chloropyrimidinyl)  —OCF_{3}  
F149 (a, b, c, and d)  4(5chloropyrimidinyl)  —Cl  
F150 (a, b, c, and d)  4(5chloropyrimidinyl)  —Br  
F151 (a, b, c, and d)  4(5chloropyrimidinyl)  —I  
F152 (a, b, c, and d)  4(5chloropyrimidinyl)  nbutyl  
F153 (a, b, c, and d)  4(5chloropyrimidinyl)  npropyl  
F154 (a, b, c, and d)  4(5chloropyrimidinyl)  isopropyl  
F155 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutyl  
F156 (a, b, c, and d)  4(5methylpyrimidinyl)  isobutyl  
F157 (a, b, c, and d)  4(5methylpyrimidinyl)  secbutyl  
F158 (a, b, c, and d)  4(5methylpyrimidinyl)  cyclohexyl  
F159 (a, b, c, and d)  4(5methylpyrimidinyl)  tertbutoxy  
F160 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropoxy  
F161 (a, b, c, and d)  4(5methylpyrimidinyl)  —CF_{3}  
F162 (a, b, c, and d)  4(5methylpyrimidinyl)  —OCF_{3}  
F163 (a, b, c, and d)  4(5methylpyrimidinyl)  —Cl  
F164 (a, b, c, and d)  4(5methylpyrimidinyl)  —Br  
F165 (a, b, c, and d)  4(5methylpyrimidinyl)  —I  
F166 (a, b, c, and d)  4(5methylpyrimidinyl)  nbutyl  
F167 (a, b, c, and d)  4(5methylpyrimidinyl)  npropyl  
F168 (a, b, c, and d)  4(5methylpyrimidinyl)  isopropyl  
F169 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutyl  
F170 (a, b, c, and d)  4(5fluoropyrimidinyl)  isobutyl  
F171 (a, b, c, and d)  4(5fluoropyrimidinyl)  secbutyl  
F172 (a, b, c, and d)  4(5fluoropyrimidinyl)  cyclohexyl  
F173 (a, b, c, and d)  4(5fluoropyrimidinyl)  tertbutoxy  
F174 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropoxy  
F175 (a, b, c, and d)  4(5fluoropyrimidinyl)  —CF_{3}  
F176 (a, b, c, and d)  4(5fluoropyrimidinyl)  —OCF_{3}  
F177 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Cl  
F178 (a, b, c, and d)  4(5fluoropyrimidinyl)  —Br  
F179 (a, b, c, and d)  4(5fluoropyrimidinyl)  —I  
F180 (a, b, c, and d)  4(5fluoropyrimidinyl)  nbutyl  
F181 (a, b, c, and d)  4(5fluoropyrimidinyl)  npropyl  
F182 (a, b, c, and d)  4(5fluoropyrimidinyl)  isopropyl  
F183 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutyl  
F184 (a, b, c, and d)  2(3chloropyrazinyl)  isobutyl  
F185 (a, b, c, and d)  2(3chloropyrazinyl)  secbutyl  
F186 (a, b, c, and d)  2(3chloropyrazinyl)  cyclohexyl  
F187 (a, b, c, and d)  2(3chloropyrazinyl)  tertbutoxy  
F188 (a, b, c, and d)  2(3chloropyrazinyl)  isopropoxy  
F189 (a, b, c, and d)  2(3chloropyrazinyl)  —CF_{3}  
F190 (a, b, c, and d)  2(3chloropyrazinyl)  —OCF_{3}  
F191 (a, b, c, and d)  2(3chloropyrazinyl)  —Cl  
F192 (a, b, c, and d)  2(3chloropyrazinyl)  —Br  
F193 (a, b, c, and d)  2(3chloropyrazinyl)  —I  
F194 (a, b, c, and d)  2(3chloropyrazinyl)  nbutyl  
F195 (a, b, c, and d)  2(3chloropyrazinyl)  npropyl  
F196 (a, b, c, and d)  2(3chloropyrazinyl)  isopropyl  
F197 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutyl  
F198 (a, b, c, and d)  2(3methylpyrazinyl)  isobutyl  
F199 (a, b, c, and d)  2(3methylpyrazinyl)  secbutyl  
F200 (a, b, c, and d)  2(3methylpyrazinyl)  cyclohexyl  
F201 (a, b, c, and d)  2(3methylpyrazinyl)  tertbutoxy  
F202 (a, b, c, and d)  2(3methylpyrazinyl)  isopropoxy  
F203 (a, b, c, and d)  2(3methylpyrazinyl)  —CF_{3}  
F204 (a, b, c, and d)  2(3methylpyrazinyl)  —OCF_{3}  
F205 (a, b, c, and d)  2(3methylpyrazinyl)  —Cl  
F206 (a, b, c, and d)  2(3methylpyrazinyl)  —Br  
F207 (a, b, c, and d)  2(3methylpyrazinyl)  —I  
F208 (a, b, c, and d)  2(3methylpyrazinyl)  nbutyl  
F209 (a, b, c, and d)  2(3methylpyrazinyl)  npropyl  
F210 (a, b, c, and d)  2(3methylpyrazinyl)  isopropyl  
F211 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutyl  
F212 (a, b, c, and d)  2(3fluoropyrazinyl)  isobutyl  
F213 (a, b, c, and d)  2(3fluoropyrazinyl)  secbutyl  
F214 (a, b, c, and d)  2(3fluoropyrazinyl)  cyclohexyl  
F215 (a, b, c, and d)  2(3fluoropyrazinyl)  tertbutoxy  
F216 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropoxy  
F217 (a, b, c, and d)  2(3fluoropyrazinyl)  —CF_{3}  
F218 (a, b, c, and d)  2(3fluoropyrazinyl)  —OCF_{3}  
F219 (a, b, c, and d)  2(3fluoropyrazinyl)  —Cl  
F220 (a, b, c, and d)  2(3fluoropyrazinyl)  —Br  
F221 (a, b, c, and d)  2(3fluoropyrazinyl)  —I  
F222 (a, b, c, and d)  2(3fluoropyrazinyl)  nbutyl  
F223 (a, b, c, and d)  2(3fluoropyrazinyl)  npropyl  
F224 (a, b, c, and d)  2(3fluoropyrazinyl)  isopropyl  
F225 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutyl  
F226 (a, b, c, and d)  3(4chloropyridazinyl)  isobutyl  
F227 (a, b, c, and d)  3(4chloropyridazinyl)  secbutyl  
F228 (a, b, c, and d)  3(4chloropyridazinyl)  cyclohexyl  
F229 (a, b, c, and d)  3(4chloropyridazinyl)  tertbutoxy  
F230 (a, b, c, and d)  3(4chloropyridazinyl)  isopropoxy  
F231 (a, b, c, and d)  3(4chloropyridazinyl)  —CF_{3}  
F232 (a, b, c, and d)  3(4chloropyridazinyl)  —OCF_{3}  
F233 (a, b, c, and d)  3(4chloropyridazinyl)  —Cl  
F234 (a, b, c, and d)  3(4chloropyridazinyl)  —Br  
F235 (a, b, c, and d)  3(4chloropyridazinyl)  —I  
F236 (a, b, c, and d)  3(4chloropyridazinyl)  nbutyl  
F237 (a, b, c, and d)  3(4chloropyridazinyl)  npropyl  
F238 (a, b, c, and d)  3(4chloropyridazinyl)  isopropyl  
F239 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutyl  
F240 (a, b, c, and d)  3(4methylpyridazinyl)  isobutyl  
F241 (a, b, c, and d)  3(4methylpyridazinyl)  secbutyl  
F242 (a, b, c, and d)  3(4methylpyridazinyl)  cyclohexyl  
F243 (a, b, c, and d)  3(4methylpyridazinyl)  tertbutoxy  
F244 (a, b, c, and d)  3(4methylpyridazinyl)  isopropoxy  
F245 (a, b, c, and d)  3(4methylpyridazinyl)  —CF_{3}  
F246 (a, b, c, and d)  3(4methylpyridazinyl)  —OCF_{3}  
F247 (a, b, c, and d)  3(4methylpyridazinyl)  —Cl  
F248 (a, b, c, and d)  3(4methylpyridazinyl)  —Br  
F249 (a, b, c, and d)  3(4methylpyridazinyl)  —I  
F250 (a, b, c, and d)  3(4methylpyridazinyl)  nbutyl  
F251 (a, b, c, and d)  3(4methylpyridazinyl)  npropyl  
F252 (a, b, c, and d)  3(4methylpyridazinyl)  isopropyl  
F253 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutyl  
F254 (a, b, c, and d)  3(4fluoropyridazinyl)  isobutyl  
F255 (a, b, c, and d)  3(4fluoropyridazinyl)  secbutyl  
F256 (a, b, c, and d)  3(4fluoropyridazinyl)  cyclohexyl  
F257 (a, b, c, and d)  3(4fluoropyridazinyl)  tertbutoxy  
F258 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropoxy  
F259 (a, b, c, and d)  3(4fluoropyridazinyl)  —CF_{3}  
F260 (a, b, c, and d)  3(4fluoropyridazinyl)  —OCF_{3}  
F261 (a, b, c, and d)  3(4fluoropyridazinyl)  —Cl  
F262 (a, b, c, and d)  3(4fluoropyridazinyl)  —Br  
F263 (a, b, c, and d)  3(4fluoropyridazinyl)  —I  
F264 (a, b, c, and d)  3(4fluoropyridazinyl)  nbutyl  
F265 (a, b, c, and d)  3(4fluoropyridazinyl)  npropyl  
F266 (a, b, c, and d)  3(4fluoropyridazinyl)  isopropyl  
F267 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutyl  
F268 (a, b, c, and d)  5(4chlorothiadiazolyl)  isobutyl  
F269 (a, b, c, and d)  5(4chlorothiadiazolyl)  secbutyl  
F270 (a, b, c, and d)  5(4chlorothiadiazolyl)  cyclohexyl  
F271 (a, b, c, and d)  5(4chlorothiadiazolyl)  tertbutoxy  
F272 (a, b, c, and d)  5(4chlorothiadiazolyl)  isopropoxy  
F273 (a, b, c, and d)  5(4chlorothiadiazolyl)  —CF_{3} 